DPP4

Summary

DPP4 (dipeptidyl peptidase 4, HGNC:3009) is a protein-coding gene on chromosome 2q24.2, encoding Dipeptidyl peptidase 4 (P27487). Cell surface glycoprotein receptor involved in the costimulatory signal essential for T-cell receptor (TCR)-mediated T-cell activation.

The DPP4 gene encodes dipeptidyl peptidase 4, which is identical to adenosine deaminase complexing protein-2, and to the T-cell activation antigen CD26. It is an intrinsic type II transmembrane glycoprotein and a serine exopeptidase that cleaves X-proline dipeptides from the N-terminus of polypeptides. Dipeptidyl peptidase 4 is highly involved in glucose and insulin metabolism, as well as in immune regulation. This protein was shown to be a functional receptor for Middle East respiratory syndrome coronavirus (MERS-CoV), and protein modeling suggests that it may play a similar role with SARS-CoV-2, the virus responsible for COVID-19.

Source: NCBI Gene 1803 — RefSeq curated summary.

At a glance

• GWAS associations: 33 (top 4% of genes corpus-wide)
• Clinical variants (ClinVar): 150 total — 1 pathogenic, 2 likely-pathogenic
• GTEx eGene: eQTL in 17 tissues, sQTL in 18 (q < 0.05)
• Drug target: yes — 17 curated mechanism-of-action drugs; 33 molecules with ChEMBL bioactivity (top 1% of genes corpus-wide)
• Approved drugs (ChEMBL mechanism of action): 11 — Alogliptin Benzoate, Anagliptin, Evogliptin, +8 more
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.90 (unconstrained)
• MANE Select transcript: NM_001935
• Interaction hub: 3,116 STRING partners (top 2% of genes corpus-wide)
• Notable: 150 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3009
Approved symbol	DPP4
Name	dipeptidyl peptidase 4
Location	2q24.2
Locus type	gene with protein product
Status	Approved
Aliases	DPPIV
Ensembl gene	ENSG00000197635
Ensembl biotype	protein_coding
OMIM	102720
Entrez	1803

Gene structure

Transcript identifiers

Ensembl transcripts: 34 — 12 protein_coding, 11 nonsense_mediated_decay, 9 retained_intron, 2 protein_coding_CDS_not_defined

MANE Select: ENST00000360534

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 4, TSL 2: 1, TSL 3: 1, TSL 4: 2, TSL 5: 2

ENST00000360534, ENST00000413651, ENST00000416189, ENST00000434918, ENST00000461836, ENST00000468903, ENST00000490286, ENST00000491591, ENST00000494507, ENST00000497461, ENST00000676479, ENST00000676624, ENST00000676768, ENST00000676810, ENST00000676996, ENST00000677015, ENST00000677212, ENST00000678522, ENST00000678566, ENST00000678583, ENST00000678668, ENST00000678740, ENST00000679104, ENST00000881342, ENST00000881343, ENST00000980209, ENST00000980210, ENST00000980211, ENST00001043100, ENST00001071929, ENST00001111167, ENST00001111168, ENST00001111169, ENST00001138191

RefSeq mRNA: 4 — MANE Select: NM_001935 NM_001379604, NM_001379605, NM_001379606, NM_001935

CCDS: CCDS2216, CCDS92882

Canonical transcript exons

ENST00000360534 — 26 exons

Exon	Start	End
ENSE00001420909	161992245	161993384
ENSE00001428031	162073976	162074215
ENSE00003469885	162017108	162017155
ENSE00003472853	162018729	162018850
ENSE00003508024	162020581	162020688
ENSE00003514636	161994961	161995034
ENSE00003524201	162019223	162019276
ENSE00003525327	162045532	162045612
ENSE00003537896	162038949	162039021
ENSE00003555173	162020229	162020296
ENSE00003557301	162038302	162038422
ENSE00003577268	162011793	162011987
ENSE00003578186	162035164	162035324
ENSE00003589684	161995300	161995372
ENSE00003590541	162046915	162047006
ENSE00003594714	162033541	162033653
ENSE00003597566	162039132	162039184
ENSE00003605030	162009241	162009295
ENSE00003610376	162022755	162022799
ENSE00003623432	162014396	162014465
ENSE00003640971	162047403	162047501
ENSE00003641984	162005745	162005809
ENSE00003643951	162016768	162016866
ENSE00003650638	162024804	162024939
ENSE00003672736	162073399	162073486
ENSE00003678443	162008562	162008661

Expression profiles

Bgee: expression breadth ubiquitous, 219 present calls, max score 98.65.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.2200 / max 926.2571, expressed in 1173 samples.

Highest expression (Bgee): calcaneal tendon, jejunal mucosa, parotid gland, tendon of biceps brachii, tendon.

Genetic regulation across tissues (GTEx eQTL / sQTL)

DPP4 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 17 tissues and its splicing (sQTL) in 18 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 35 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Cells Cultured fibroblasts	sqtl	1.4e-81	-3.08	2:162047503:T:C
Adipose Visceral Omentum	sqtl	2.1e-38	-2.36	2:162047503:T:C
Adipose Subcutaneous	sqtl	4.9e-36	-2.41	2:162047503:T:C
Lung	sqtl	6.9e-36	-2.35	2:162047503:T:C
Breast Mammary Tissue	sqtl	1.4e-22	-1.95	2:162047503:T:C
Nerve Tibial	sqtl	1.9e-22	-1.82	2:162047503:T:C
Colon Transverse	sqtl	5.3e-20	-2.06	2:162047503:T:C
Colon Sigmoid	sqtl	1.8e-18	-2.28	2:162047503:T:C
Skin Sun Exposed Lower leg	sqtl	1.8e-16	-1.52	2:162047503:T:C
Adrenal Gland	eqtl	1.9e-16	+0.51	2:162115829:A:G
Lung	eqtl	7.1e-08	+0.20	2:162118384:G:A
Cells EBV-transformed lymphocytes	sqtl	2.2e-07	-2.06	2:161896660:T:G
Cells EBV-transformed lymphocytes	eqtl	1.3e-05	+0.28	2:162073199:T:G
Prostate	sqtl	3.1e-05	+2.40	2:162047503:T:C
Colon Transverse	eqtl	3.4e-05	+0.29	2:162061561:G:A
Brain Cortex	eqtl	1.7e-04	+0.26	2:162070034:C:T
Thyroid	eqtl	1.9e-04	-0.18	2:162074215:T:G
Brain Frontal Cortex BA9	eqtl	2.1e-04	-0.23	2:162064625:G:A
Minor Salivary Gland	sqtl	3.7e-04	+2.20	2:162047503:T:C
Adrenal Gland	sqtl	5.8e-04	-1.55	2:162047503:T:C

FANTOM5 promoters

showing 10 of 19 alternative TSS:

Promoter ID	TPM avg	Samples expressed
31520	5.4911	837
31523	4.2255	782
31518	2.4864	650
31521	2.0881	462
31519	1.2992	492
31522	0.5043	249
31524	0.4916	262
31529	0.4781	205
31525	0.3196	135
31516	0.3054	170

Top tissues by expression

showing 100 of 278 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	98.65	gold quality
jejunal mucosa	UBERON:0000399	98.32	gold quality
parotid gland	UBERON:0001831	98.29	gold quality
tendon of biceps brachii	UBERON:0008188	98.13	gold quality
tendon	UBERON:0000043	97.48	gold quality
duodenum	UBERON:0002114	95.67	gold quality
nephron tubule	UBERON:0001231	95.62	gold quality
placenta	UBERON:0001987	94.00	gold quality
stromal cell of endometrium	CL:0002255	92.62	gold quality
parietal pleura	UBERON:0002400	92.59	gold quality
seminal vesicle	UBERON:0000998	92.06	gold quality
pleura	UBERON:0000977	91.04	gold quality
renal glomerulus	UBERON:0000074	90.61	gold quality
metanephric glomerulus	UBERON:0004736	90.18	gold quality
adult mammalian kidney	UBERON:0000082	89.82	gold quality
visceral pleura	UBERON:0002401	89.80	gold quality
skin of hip	UBERON:0001554	89.59	gold quality
kidney	UBERON:0002113	89.30	gold quality
kidney epithelium	UBERON:0004819	89.20	gold quality
small intestine Peyer’s patch	UBERON:0003454	88.80	gold quality
small intestine	UBERON:0002108	88.70	gold quality
rectum	UBERON:0001052	88.53	gold quality
cortex of kidney	UBERON:0001225	87.75	gold quality
synovial joint	UBERON:0002217	87.65	gold quality
germinal epithelium of ovary	UBERON:0001304	87.07	gold quality
mucosa of sigmoid colon	UBERON:0004993	86.97	gold quality
colonic epithelium	UBERON:0000397	86.18	gold quality
metanephros	UBERON:0000081	86.05	gold quality
prostate gland	UBERON:0002367	86.03	gold quality
liver	UBERON:0002107	86.01	gold quality
colonic mucosa	UBERON:0000317	85.79	gold quality
upper leg skin	UBERON:0004262	85.31	gold quality
amniotic fluid	UBERON:0000173	84.92	gold quality
tibia	UBERON:0000979	84.68	gold quality
decidua	UBERON:0002450	84.58	silver quality
jejunum	UBERON:0002115	84.17	gold quality
metanephros cortex	UBERON:0010533	84.13	gold quality
renal medulla	UBERON:0000362	84.03	gold quality
islet of Langerhans	UBERON:0000006	83.91	gold quality
triceps brachii	UBERON:0001509	83.61	silver quality
periodontal ligament	UBERON:0008266	82.94	silver quality
right lobe of liver	UBERON:0001114	82.35	gold quality
gluteal muscle	UBERON:0002000	82.32	gold quality
omental fat pad	UBERON:0010414	81.21	gold quality
peritoneum	UBERON:0002358	81.16	gold quality
sperm	CL:0000019	81.11	gold quality
male germ cell	CL:0000015	81.04	gold quality
subcutaneous adipose tissue	UBERON:0002190	80.94	gold quality
intestine	UBERON:0000160	80.47	gold quality
adipose tissue of abdominal region	UBERON:0007808	80.16	gold quality
ileal mucosa	UBERON:0000331	79.90	gold quality
mucosa of transverse colon	UBERON:0004991	79.66	gold quality
saliva-secreting gland	UBERON:0001044	79.63	gold quality
blood	UBERON:0000178	79.62	gold quality
gall bladder	UBERON:0002110	79.41	gold quality
adrenal tissue	UBERON:0018303	79.22	gold quality
upper lobe of lung	UBERON:0008948	79.07	gold quality
lung	UBERON:0002048	79.00	gold quality
upper lobe of left lung	UBERON:0008952	78.95	gold quality
type B pancreatic cell	CL:0000169	78.76	gold quality
olfactory bulb	UBERON:0002264	78.70	gold quality
lower lobe of lung	UBERON:0008949	77.99	gold quality
spleen	UBERON:0002106	77.79	gold quality
connective tissue	UBERON:0002384	77.57	gold quality
layer of synovial tissue	UBERON:0007616	77.53	gold quality
smooth muscle tissue	UBERON:0001135	77.52	gold quality
large intestine	UBERON:0000059	77.41	gold quality
adipose tissue	UBERON:0001013	77.33	gold quality
colon	UBERON:0001155	77.19	gold quality
lymph node	UBERON:0000029	76.50	gold quality
transverse colon	UBERON:0001157	76.49	gold quality
endometrium	UBERON:0001295	76.44	gold quality
diaphragm	UBERON:0001103	76.30	gold quality
granulocyte	CL:0000094	76.13	gold quality
skin of leg	UBERON:0001511	75.83	gold quality
zone of skin	UBERON:0000014	75.61	gold quality
thoracic mammary gland	UBERON:0005200	75.33	gold quality
vermiform appendix	UBERON:0001154	75.29	gold quality
cervix epithelium	UBERON:0004801	75.24	gold quality
sigmoid colon	UBERON:0001159	75.15	gold quality
mammary gland	UBERON:0001911	75.14	gold quality
cervix squamous epithelium	UBERON:0006922	74.98	gold quality
minor salivary gland	UBERON:0001830	74.86	gold quality
tibial nerve	UBERON:0001323	74.85	gold quality
caecum	UBERON:0001153	74.84	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	74.56	gold quality
right lung	UBERON:0002167	74.00	gold quality
apex of heart	UBERON:0002098	73.95	gold quality
epithelium of bronchus	UBERON:0002031	73.90	gold quality
pancreatic ductal cell	CL:0002079	73.75	silver quality
bronchial epithelial cell	CL:0002328	73.75	gold quality
tonsil	UBERON:0002372	73.74	gold quality
skin of abdomen	UBERON:0001416	73.52	gold quality
nasal cavity mucosa	UBERON:0001826	73.51	gold quality
bronchus	UBERON:0002185	73.50	gold quality
pancreas	UBERON:0001264	73.43	gold quality
heart left ventricle	UBERON:0002084	73.41	gold quality
cortical plate	UBERON:0005343	73.40	gold quality
mammary duct	UBERON:0001765	73.19	silver quality
cardiac ventricle	UBERON:0002082	73.19	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-MTAB-7249	yes	256.74
E-GEOD-81608	yes	132.47
E-MTAB-5061	yes	29.80
E-HCAD-10	yes	27.87
E-GEOD-81547	yes	20.26
E-ENAD-27	yes	11.73
E-GEOD-83139	yes	10.33
E-GEOD-124858	no	173.47
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 74 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Parathyroid gland	tissue	146.6	high
Small intestine	tissue	130.0	high
Placenta	tissue	126.0	medium
Duodenum	tissue	100.8	high
Prostate	tissue	100.7	high
Kidney	tissue	88.6	high
Salivary gland	tissue	79.6	high
Liver	tissue	53.5	high
Seminal vesicle	tissue	22.1	high
Rectum	tissue	15.9	medium
Lung	tissue	15.1	not detected
Ovary	tissue	13.9	not detected
Colon	tissue	13.7	medium
Thymus	tissue	11.5
Spleen	tissue	10.6	not detected
Superior colliculi	tissue	10.3
Cervix	tissue	10.2	not detected
Olfactory bulb	tissue	8.8
Adipose tissue	tissue	8.2	not detected
Breast	tissue	7.9	not detected
Stomach 1	tissue	7.2	not detected
Fallopian tube	tissue	6.9	low
Gallbladder	tissue	6.3	high
Lymph node	tissue	5.5	not detected
Urinary bladder	tissue	5.3	not detected
Appendix	tissue	5.0	not detected
Skin 1	tissue	4.8	low
Thyroid gland	tissue	4.7	not detected
Tonsil	tissue	4.2	not detected
Epididymis	tissue	3.8	not detected
Tongue	tissue	3.7
Hippocampal formation	tissue	3.6
Entorhinal cortex	tissue	3.6
Endometrium 1	tissue	3.4	not detected
Pancreas	tissue	3.3	medium
Cerebellum	tissue	3.3	not detected
Cerebral cortex	tissue	3.1	not detected
Occipital cortex	tissue	3.1
Vagina	tissue	3.0	not detected
Retrosplenial and cingulate cortex	tissue	3.0
Retrosplenial cortex	tissue	3.0
Esophagus	tissue	2.8	not detected
Smooth muscle	tissue	2.8	not detected
Somatosensory cortex	tissue	2.8
Prefrontal cortex	tissue	2.7
Motor cortex	tissue	2.7
Insular cortex	tissue	2.6
Temporal cortex	tissue	2.5
Frontal cortex	tissue	2.1
Amygdala	tissue	1.8
Spinal cord	tissue	1.7
Ventral forebrain	tissue	1.6
Septum	tissue	1.6
Heart muscle	tissue	1.5	not detected
Basal ganglia	tissue	1.3	not detected
Adrenal gland	tissue	1.3	not detected
Testis	tissue	1.2	not detected
Thalamus	tissue	1.2
Putamen	tissue	1.1
Midbrain	tissue	1.0

Brain sub-regions (HPA Brain Atlas): detected in 96; highest nTPM — Subiculum (3.0), Dorsal hippocampus (2.2), Ventral hippocampus (2.0), Dorsal spinal cord (1.7), Anterior thalamic nucleus, ventral (1.5).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CDX2, HNF1A, HNF1B, MYC, USF1, USF2

Functional genomics

gnomAD constraint: pLI 1.65e-17, LOEUF 0.901, missense Z 0.645 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000360534 — one region, missense o/e 1.01.

Literature-anchored findings (GeneRIF, showing 40)

• Soluble CD26 induces T cell proliferation in Antigen presenting cells (PMID:11739489)
• Intestinal dipeptidyl peptidase IV is efficiently sorted to the apical membrane through the concerted action of N- and O-glycans (PMID:11773049)
• DPPIV activity is depressed in individuals with hypertension during acute ACEI-associated angioedema. (PMID:11882590)
• Clustered charged amino acids of human adenosine deaminase comprise a functional epitope for binding the adenosine deaminase complexing protein CD26/dipeptidyl peptidase IV. (PMID:11901152)
• expression of the seprase-DPPIV complex is restricted to migratory cells involved in wound closure (PMID:12023964)
• Decrease of serum dipeptidylpeptidase activity in severe sepsis patients: relationship to procalcitonin. (PMID:12031601)
• chromogranin B(586-602) peptide can serve as a substrate for the lymphocyte surface glycoprotein CD26, also known as dipeptidyl peptidase IV (DPP IV), generating a new peptide ER-15 (CgB(588-602)) (PMID:12047913)
• DPIV mediated transcellular proteolysis (PMID:12095981)
• galectin-3 and CD26/DPPIV as preoperative diagnostic markers for thyroid nodules (PMID:12112826)
• CD26 interferes with transduction pathway(s) needed for the maturation of T cells and plays an important role in T lymphocyte homeostasis in peripheral blood. (PMID:12175726)
• examination of expression and enzymatic activity in recipients of kidney allografts (PMID:12176563)
• Involvement in extravillous trophoblast invasion and differentiation (PMID:12213886)
• Increased expression in human mesothelial cells by malignant ascites from ovarian carcinoma patients (PMID:12239451)
• REVIEW: expression and effects on immune cells (PMID:12437097)
• The process of CXCL12/SDF-1 alpha cleavage by CD26/DPPIV on a subpopulation of cord blood CD34+ cells represents a novel regulatory mechanism in hemopoietic stem and progenitor cells for the migration, homing, and mobilization of these cells. (PMID:12471135)
• The CD26 structure indicates how substrate specificity is achieved and reveals a new and unexpected opening to the active site. (PMID:12483204)
• catalytic properties and inhibition of this proline-specific enzyme (PMID:12529175)
• Review. CD26 has an essential role in human T-cell activation, as well as its ability to regulate the biological effects of selected chemokines through its DPPIV activity. (PMID:12579300)
• crystals of dipeptidylpeptidase IV belongs to the orthorhombic space group P2(1)2(1)2(1), with unit-cell parameters a = 118.04, b = 125.92, c = 136.84 A, and diffracts beyond 2.6 A resolution (PMID:12595736)
• Expressed in normal endometrial glandular cells, but expression in endometrial adenocarcinoma is down-regulated with increasing grade. Regulatory role in neoplastic transformation and progression of endometrial adenocarcinomas. (PMID:12634639)
• report the structure of human dipeptidyl peptidase IV especially focusing on a unique eight-bladed beta-propeller domain; discuss the way for the access of the substrate to this domain (PMID:12646248)
• an examination of the substrate specificity of this enzyme (REVIEW) (PMID:12675218)
• The active site of this enzyme is examined and compared with Porphyromonas gingivalis. (PMID:12675220)
• The kinetics of this enzyme are examined, after cloning in Pichia pastoris. (PMID:12675229)
• Protein-protein interactions dependent on this enzyme are investigated using surface plasmon resonance. (PMID:12675231)
• This protein acts synergistically with APN to regulate T cell function. (PMID:12675232)
• An increase in this enzyme is associated with graft rejection. Inhibition of this enzyme prevents kieney graft rejection. (PMID:12675233)
• plays a role in the digestion of an immunodominant epitope in celiac disease (PMID:12675238)
• This enzyme is expressed in cutaneous infiltrates from patients with cutaneous T-cell lymphoma. (PMID:12675243)
• This enzyme is expressed in endometrial adenocarcinoma and is negatively correlated with tumor grade. (PMID:12675245)
• Adhesion to mesothelial is increased by overexpression of dipeptidyl peptidase IV. (PMID:12675246)
• This enzyme suppresses ovarian carcinoma in peritoneal dissemination in vitro and in vivo. (PMID:12675247)
• This enzyme is active in prostatic secretions and prostate cancer. (PMID:12675248)
• This enzyme is a marker of mood in anorexia nervosa and bulimia nervosa patients. (PMID:12675253)
• Serum levels are decreased in patients with Crohn and inflammatory bowel disease who are clinically depressed. (PMID:12675254)
• elevated serum levels in chronic hepatitis C and other viral infections suggest that this activity originates not only from the liver, but also from other sources such as peripheral blood cells involved in the control of viral infections. (PMID:12727530)
• Increased adhesion of ovarian carcinoma cells to mesothelial cells by overexpression of dipeptidyl peptidase IV. (PMID:12767062)
• This enzyme is a marker in thyroid tumors. (PMID:12820316)
• structure of the binary complex with 1-[([2-[(5-iodopyridin-2-yl)amino]-ethyl]amino)-acetyl]-2-cyano-(S)-pyrrolidine has been solved, revealing the nature of the covalent interaction with the active-site serine (PMID:12832764)
• strong physical linkage of CD26 with CD45RA outside lipid rafts may be responsible for the attenuation of T-cell activation signaling through CD26 (PMID:14525771)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	zgc:136971	ENSDARG00000055970
danio_rerio	dpp4	ENSDARG00000079420
mus_musculus	Dpp4	ENSMUSG00000035000
rattus_norvegicus	Dpp4	ENSRNOG00000030763
drosophila_melanogaster	ome	FBGN0259175
caenorhabditis_elegans		WBGENE00001054

Paralogs (6): DPP8 (ENSG00000074603), FAP (ENSG00000078098), DPP6 (ENSG00000130226), DPP9 (ENSG00000142002), APEH (ENSG00000164062), DPP10 (ENSG00000175497)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:94919) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 18 distinct phenotype terms.

Mouse phenotype (MP)	Records
improved glucose tolerance	3
decreased lymphocyte cell number	2
increased susceptibility to Coronaviridae infection	2
increased neutrophil cell number	1
increased monocyte cell number	1
lung hemorrhage	1
decreased body weight	1
lung inflammation	1
respiratory distress	1
increased circulating insulin level	1
increased circulating glucagon level	1
increased insulin secretion	1
abnormal auditory brainstem response	1
increased susceptibility to weight loss	1
pulmonary alveolar edema	1
increased susceptibility to pulmonary hyaline membrane formation	1
decreased susceptibility to Coronaviridae infection induced morbidity/mortality	1
increased susceptibility to Coronaviridae infection induced morbidity/mortality	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Microsporum canis	A0S5V9	100.0%	Diamond
Aspergillus flavus NRRL3357	B8N076	100.0%	Diamond
Microsporum canis CBS 113480	C5FJE3	100.0%	Diamond
Blastomyces dermatitidis ER-3	C5GVF3	100.0%	Diamond
Blastomyces gilchristii SLH14081	C5JC30	100.0%	Diamond
Coccidioides posadasii C735 delta SOWgp	C5P334	100.0%	Diamond
Histoplasma capsulatum H143	C6HRC7	100.0%	Diamond
Coccidioides posadasii str. Silveira	E9CUF4	100.0%	Diamond
Histoplasma capsulatum var. duboisii H88	F0U7H7	100.0%	Diamond
Aspergillus oryzae RIB40	Q2UH35	100.0%	Diamond
Aspergillus fumigatus A1163	B0XYK8	99.7%	Diamond
Aspergillus fumigatus Af293	Q4WPH9	99.7%	Diamond
Paracoccidioides brasiliensis Pb03	C0S7H1	99.6%	Diamond
Paracoccidioides brasiliensis Pb18	C1FZL3	99.6%	Diamond
Trichophyton equinum	A7UKV8	99.5%	Diamond
Trichophyton tonsurans	B6V868	99.5%	Diamond
Aspergillus niger CBS 513.88	A2QEK7	99.3%	Diamond
Aspergillus niger	Q96VT7	99.3%	Diamond
Pan troglodytes	Q5IS50	99.0%	Diamond
Histoplasma capsulatum G186AR	C0NUQ8	98.9%	Diamond
Trichophyton benhamiae CBS 112371	D4APE2	98.6%	Diamond
Trichophyton verrucosum HKI 0517	D4DCG0	98.4%	Diamond
Aspergillus fischeri NRRL 181	A1CX29	98.0%	Diamond
Trichophyton rubrum	Q5J6J3	97.9%	Diamond
Histoplasma mississippiense	A6RBI0	97.0%	Diamond
Paracoccidioides lutzii Pb01	C1GT79	96.5%	Diamond
Sordaria macrospora k-hell	D1Z9B4	94.5%	Diamond
Neurospora crassa OR74A	Q7SHU8	94.5%	Diamond
Bos taurus	A5D7B7	93.9%	Diamond
Metarhizium acridum CQMa 102	E9ED72	93.2%	Diamond
Metarhizium robertsii ARSEF 23	E9ETL5	93.2%	Diamond
Sus scrofa	P22411	91.0%	Diamond
Felis catus	Q9N2I7	88.0%	Diamond
Nannizzia gypsea CBS 118893	E4UYL6	87.5%	Diamond
Vespula vulgaris	B1A4F7	86.2%	Diamond
Vespa velutina	P0DRB8	86.2%	Diamond
Aspergillus clavatus NRRL 1	A1CHP1	83.2%	Diamond
Uncinocarpus reesii 1704	C4JHY5	75.4%	Diamond
Aspergillus terreus NIH2624	Q0CXB1	74.4%	Diamond
Aspergillus nidulans FGSC A4	Q5AZ42	71.4%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
GCG	protein-coding	2641
SLC4A10	protein-coding	57282
DPP4-DT	ncRNA	100131604
FAP	protein-coding	2191

Protein

Protein identifiers

Dipeptidyl peptidase 4 — P27487 (reviewed: P27487)

Alternative names: ADABP, Adenosine deaminase complexing protein 2, Dipeptidyl peptidase IV, T-cell activation antigen CD26, TP103

All UniProt accessions (9): A0A7I2V2I2, A0A7I2V2R5, A0A7I2V2X8, A0A7I2V3F5, A0A7I2V501, A0A7I2V5R8, P27487, F8WBB6, F8WE17

UniProt curated annotations — full annotation on UniProt →

Function. Cell surface glycoprotein receptor involved in the costimulatory signal essential for T-cell receptor (TCR)-mediated T-cell activation. Acts as a positive regulator of T-cell coactivation, by binding at least ADA, CAV1, IGF2R, and PTPRC. Its binding to CAV1 and CARD11 induces T-cell proliferation and NF-kappa-B activation in a T-cell receptor/CD3-dependent manner. Its interaction with ADA also regulates lymphocyte-epithelial cell adhesion. In association with FAP is involved in the pericellular proteolysis of the extracellular matrix (ECM), the migration and invasion of endothelial cells into the ECM. May be involved in the promotion of lymphatic endothelial cells adhesion, migration and tube formation. When overexpressed, enhanced cell proliferation, a process inhibited by GPC3. Also acts as a serine exopeptidase with a dipeptidyl peptidase activity that regulates various physiological processes by cleaving peptides in the circulation, including many chemokines, mitogenic growth factors, neuropeptides and peptide hormones such as brain natriuretic peptide 32. Removes N-terminal dipeptides sequentially from polypeptides having unsubstituted N-termini provided that the penultimate residue is proline. (Microbial infection) Acts as a receptor for human coronavirus MERS-CoV-2.

Subunit / interactions. Monomer. Homodimer. Heterodimer with Seprase (FAP). Requires homodimerization for optimal dipeptidyl peptidase activity and T-cell costimulation. Found in a membrane raft complex, at least composed of BCL10, CARD11, DPP4 and IKBKB. Associates with collagen. Interacts with PTPRC; the interaction is enhanced in an interleukin-12-dependent manner in activated lymphocytes. Interacts (via extracellular domain) with ADA; does not inhibit its dipeptidyl peptidase activity. Interacts with CAV1 (via the N-terminus); the interaction is direct. Interacts (via cytoplasmic tail) with CARD11 (via PDZ domain); its homodimerization is necessary for interaction with CARD11. Interacts with IGF2R; the interaction is direct. Interacts with GPC3. Interacts with human coronavirus-EMC spike protein and acts as a receptor for this virus. (Microbial infection) Interacts with MERS coronavirus/MERS-CoV spike protein.

Subcellular location. Secreted Cell membrane. Apical cell membrane. Cell projection. Invadopodium membrane. Lamellipodium membrane. Cell junction. Membrane raft.

Tissue specificity. Expressed specifically in lymphatic vessels but not in blood vessels in the skin, small intestine, esophagus, ovary, breast and prostate glands. Not detected in lymphatic vessels in the lung, kidney, uterus, liver and stomach (at protein level). Expressed in the poorly differentiated crypt cells of the small intestine as well as in the mature villous cells. Expressed at very low levels in the colon.

Post-translational modifications. The soluble form (Dipeptidyl peptidase 4 soluble form also named SDPP) derives from the membrane form (Dipeptidyl peptidase 4 membrane form also named MDPP) by proteolytic processing. N- and O-Glycosylated. Phosphorylated. Mannose 6-phosphate residues in the carbohydrate moiety are necessary for interaction with IGF2R in activated T-cells. Mannose 6-phosphorylation is induced during T-cell activation.

Activity regulation. Inhibited by GPC3 and diprotin A.

Domain organisation. The extracellular cysteine-rich region is necessary for association with collagen, dimer formation and optimal dipeptidyl peptidase activity.

Induction. Up-regulated by IL12/interleukin-12 on activated T-cells. IL12-activated cells expressed enhanced levels of DPP4 but not mRNAs. Down-regulated by TNF. Up-regulated in migratory endothelial cells and in the invasive endothelial cells in tumors. Induced by hypoxia.

Miscellaneous. Level of plasma concentrations of the soluble form (SDPP) can be managed as a colon carcinoma diagnostic and prognostic marker.

Similarity. Belongs to the peptidase S9B family. DPPIV subfamily.

RefSeq proteins (4): NP_001366533, NP_001366534, NP_001366535, NP_001926* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001375	Peptidase_S9_cat	Domain
IPR002469	Peptidase_S9B_N	Domain
IPR002471	Pept_S9_AS	Active_site
IPR029058	AB_hydrolase_fold	Homologous_superfamily
IPR050278	Serine_Prot_S9B/DPPIV	Family

Pfam: PF00326, PF00930

Enzyme classification (BRENDA)

• EC 3.4.14.5 — dipeptidyl-peptidase IV (BRENDA: 38 organisms, 518 substrates, 2236 inhibitors, 199 Km, 147 kcat entries)

Substrate kinetics (BRENDA)

105 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
GLY-PRO-4-NITROANILIDE	0.06–44.08	34
ALA-PRO-7-AMIDO-4-METHYLCOUMARIN	0.0003–0.022	11
ALA-PRO-7-AMIDO-4-TRIFLUOROMETHYLCOUMARIN	0.013–0.015	10
GLY-PRO-P-NITROANILIDE	0.05–3.1	9
GLY-PRO-7-AMIDO-4-METHYLCOUMARIN	0.0069–0.57	8
GLY-L-PRO-4-NITROANILIDE	0.076–0.3	5
ALA-PRO-7-AMIDO-4-TRIFLUOROMETHYL COUMARIN	0.0148–0.0172	3
LYS-PRO-7-AMIDO-4-METHYLCOUMARIN	0.0001–0.035	3
ALA-ALA-2-NAPHTHYLAMIDE	0.82–1	2
GLU-PRO-7-AMIDO-4-METHYLCOUMARIN	0.003–0.457	2
GLY-L-PRO-7-AMIDO-4-METHYLCOUMARIN	0.0046–0.0194	2
GLY-L-PRO-RHODAMINE 110-(N-PENTYL)MALEIMIDE	0.0013	2
GLY-PRO-4-METHOXY-BETA-NAPHTHYLAMIDE	0.5–1	2
L-ALA-L-PRO-4-NITROANILIDE	0.06–0.4	2
L-ALA-L-PRO-P-NITROANILIDE	0.099–0.432	2

UniProt features (137 total): strand 60, helix 24, mutagenesis site 13, turn 12, glycosylation site 9, disulfide bond 5, sequence conflict 5, active site 3, chain 2, topological domain 2, sequence variant 1, transmembrane region 1

Structure

Experimental structures (PDB)

showing 30 of 121 structures by resolution:

PDB	Title	Method	Resolution (Å)
4A5S	CRYSTAL STRUCTURE OF HUMAN DPP4 IN COMPLEX WITH A NOVAL HETEROCYCLIC DPP4 INHIBITOR	X-RAY DIFFRACTION	1.62
4N8D	DPP4 complexed with syn-7aa	X-RAY DIFFRACTION	1.65
5T4B	Human DPP4 in complex with a ligand 34a	X-RAY DIFFRACTION	1.76
5T4E	Human DPP4 in complex with ligand 19a	X-RAY DIFFRACTION	1.77
6B1E	The structure of DPP4 in complex with Vildagliptin	X-RAY DIFFRACTION	1.77
1PFQ	crystal structure of human apo dipeptidyl peptidase IV / CD26	X-RAY DIFFRACTION	1.9
4PNZ	Human dipeptidyl peptidase IV/CD26 in complex with the long-acting inhibitor Omarigliptin …	X-RAY DIFFRACTION	1.9
5T4F	Human DPP4 in complex with ligand 34p	X-RAY DIFFRACTION	1.9
6B1O	The structure of DPP4 in complex with Vildagliptin Analog	X-RAY DIFFRACTION	1.91
5I7U	Human DPP4 in complex with a novel tricyclic hetero-cycle inhibitor	X-RAY DIFFRACTION	1.95
9LBT	DPPIV-VAMP	X-RAY DIFFRACTION	1.99
1TK3	Crystal Structure Of Human Apo Dipeptidyl Peptidase IV/CD26	X-RAY DIFFRACTION	2
2BGR	Crystal structure of HIV-1 Tat derived nonapeptides Tat(1-9) bound to the active site of …	X-RAY DIFFRACTION	2
2G63	Crystal structure of human dipeptidyl peptidase IV (DPPIV) complexed with …	X-RAY DIFFRACTION	2
3D4L	Human dipeptidyl peptidase IV/CD26 in complex with a novel inhibitor	X-RAY DIFFRACTION	2
3EIO	Crystal Structure Analysis of DPPIV Inhibitor	X-RAY DIFFRACTION	2
3HAC	The structure of DPP-4 in complex with piperidine fused imidazopyridine 34	X-RAY DIFFRACTION	2
3SWW	Crystal structure of human dpp-iv in complex with …	X-RAY DIFFRACTION	2
5ISM	Human DPP4 in complex with a novel 5,5,6-tricyclic pyrrolidine inhibitor	X-RAY DIFFRACTION	2
3C45	Human dipeptidyl peptidase IV/CD26 in complex with a fluoroolefin inhibitor	X-RAY DIFFRACTION	2.05
1NU6	Crystal structure of human Dipeptidyl Peptidase IV (DPP-IV)	X-RAY DIFFRACTION	2.1
1R9M	Crystal Structure of Human Dipeptidyl Peptidase IV at 2.1 Ang. Resolution.	X-RAY DIFFRACTION	2.1
1X70	HUMAN DIPEPTIDYL PEPTIDASE IV IN COMPLEX WITH A BETA AMINO ACID INHIBITOR	X-RAY DIFFRACTION	2.1
2OGZ	Crystal structure of DPP-IV complexed with Lilly aryl ketone inhibitor	X-RAY DIFFRACTION	2.1
2QT9	Human dipeptidyl peptidase iv/cd26 in complex with a 4-aryl cyclohexylalanine inhibitor	X-RAY DIFFRACTION	2.1
3HAB	The structure of DPP4 in complex with piperidine fused benzimidazole 25	X-RAY DIFFRACTION	2.1
3VJM	Crystal structure of human depiptidyl peptidase IV (DPP-4) in complex with a …	X-RAY DIFFRACTION	2.1
2IIV	Human dipeptidyl peptidase 4 in complex with a diazepan-2-one inhibitor	X-RAY DIFFRACTION	2.15
1RWQ	Human Dipeptidyl peptidase IV in complex with …	X-RAY DIFFRACTION	2.2
1U8E	HUMAN DIPEPTIDYL PEPTIDASE IV/CD26 MUTANT Y547F	X-RAY DIFFRACTION	2.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P27487-F1	96.45	0.94

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Peptidases, Serine-type peptidases, CD markers, Transporters, Accessory Factors Involved in Transport, Predicted secreted proteins, Predicted intracellular proteins, Plasma proteins, FDA approved drug targets, Small molecule drugs

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH enhanced

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (3)

Position	Role
630	charge relay system
708	charge relay system
740	charge relay system

Disulfide bonds (5)

Type	Positions
Disulfide bond	328–339, 385–394, 444–447, 454–472, 649–762

Glycosylation sites (9)

Type	Positions
N-linked (glcnac…) asparagine	150, 219, 229, 281, 321, 520, 685, 85, 92

Mutagenesis-validated functional residues (13)

Position	Phenotype
85	does not inhibit dipeptidyl peptidase activity, interaction with ada and homodimer formation.
92	does not inhibit dipeptidyl peptidase activity, interaction with ada and homodimer formation.
150	does not inhibit dipeptidyl peptidase activity, interaction with ada and homodimer formation.
205	inhibits dipeptidyl peptidase activity.
206	inhibits dipeptidyl peptidase activity.
219	does not inhibit dipeptidyl peptidase activity, interaction with ada and homodimer formation.
229	does not inhibit dipeptidyl peptidase activity, interaction with ada and homodimer formation.
281	does not inhibit dipeptidyl peptidase activity, interaction with ada and homodimer formation.
321	does not inhibit dipeptidyl peptidase activity, interaction with ada and homodimer formation.
520	does not inhibit dipeptidyl peptidase activity, interaction with ada and homodimer formation.
685	does not inhibit dipeptidyl peptidase activity, interaction with ada and homodimer formation.
750	inhibits weakly homodimerization and dipeptidyl peptidase activity.
750	inhibits strongly homodimerization, dipeptidyl peptidase activity, interaction with card11 and t-cell costimulation activity.

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 5; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

5 pathways:

ID	Pathway	Evidence
R-HSA-381771	Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1)	curated
R-HSA-400511	Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP)	curated
R-HSA-400508	Incretin synthesis, secretion, and inactivation	—
R-HSA-392499	Metabolism of proteins	—
R-HSA-2980736	Peptide hormone metabolism	—

MSigDB gene sets: 432 (showing top): MODULE_172, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_BEHAVIOR, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CELL_CHEMOTAXIS, GOCC_VACUOLAR_MEMBRANE, GOBP_MEMBRANE_FUSION, GOBP_LYMPHOCYTE_COSTIMULATION, GOBP_REGULATION_OF_HORMONE_LEVELS, GOCC_CELL_SURFACE, GOBP_VESICLE_MEDIATED_TRANSPORT, CHANDRAN_METASTASIS_DN, LEE_LIVER_CANCER_CIPROFIBRATE_DN, GOBP_REGULATION_OF_LEUKOCYTE_MIGRATION, GOBP_REGULATION_OF_EXTRACELLULAR_MATRIX_ORGANIZATION

GO Biological Process (17): response to hypoxia (GO:0001666), proteolysis (GO:0006508), cell adhesion (GO:0007155), positive regulation of cell population proliferation (GO:0008284), negative regulation of extracellular matrix disassembly (GO:0010716), peptide hormone processing (GO:0016486), receptor-mediated endocytosis of virus by host cell (GO:0019065), T cell costimulation (GO:0031295), regulation of cell-cell adhesion mediated by integrin (GO:0033632), T cell activation (GO:0042110), endothelial cell migration (GO:0043542), symbiont entry into host cell (GO:0046718), receptor-mediated virion attachment to host cell (GO:0046813), membrane fusion (GO:0061025), negative regulation of neutrophil chemotaxis (GO:0090024), glucagon processing (GO:0120116), negative chemotaxis (GO:0050919)

GO Molecular Function (13): virus receptor activity (GO:0001618), protease binding (GO:0002020), aminopeptidase activity (GO:0004177), serine-type endopeptidase activity (GO:0004252), signaling receptor binding (GO:0005102), serine-type peptidase activity (GO:0008236), dipeptidyl-peptidase activity (GO:0008239), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), chemorepellent activity (GO:0045499), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (15): extracellular region (GO:0005576), lysosomal membrane (GO:0005765), plasma membrane (GO:0005886), focal adhesion (GO:0005925), cell surface (GO:0009986), membrane (GO:0016020), apical plasma membrane (GO:0016324), lamellipodium (GO:0030027), endocytic vesicle (GO:0030139), lamellipodium membrane (GO:0031258), membrane raft (GO:0045121), intercellular canaliculus (GO:0046581), extracellular exosome (GO:0070062), cell projection (GO:0042995), anchoring junction (GO:0070161)

Reactome top-level categories

3 top-level categories:

Category	Pathways
Incretin synthesis, secretion, and inactivation	2
Metabolism of proteins	1
Peptide hormone metabolism	1

GO top-level categories

showing 60 of 67 GO namespaces:

Category	Terms
cellular anatomical structure	4
symbiont entry into host cell	2
exopeptidase activity	2
protein binding	2
response to stress	1
response to decreased oxygen levels	1
protein metabolic process	1
cellular process	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
regulation of extracellular matrix disassembly	1
extracellular matrix disassembly	1
negative regulation of extracellular matrix organization	1
hormone metabolic process	1
signaling receptor ligand precursor processing	1
receptor-mediated endocytosis	1
endocytosis involved in viral entry into host cell	1
lymphocyte costimulation	1
positive regulation of T cell activation	1
regulation of cell-cell adhesion	1
regulation of cell adhesion mediated by integrin	1
cell-cell adhesion mediated by integrin	1
lymphocyte activation	1
cell migration	1
viral life cycle	1
symbiont entry into host	1
signaling receptor binding	1
virion attachment to host cell	1
membrane organization	1
neutrophil chemotaxis	1
negative regulation of granulocyte chemotaxis	1
regulation of neutrophil chemotaxis	1
negative regulation of neutrophil migration	1
peptide hormone processing	1
chemotaxis	1
exogenous protein binding	1
enzyme binding	1
endopeptidase activity	1
serine-type peptidase activity	1
peptidase activity	1
serine hydrolase activity	1
identical protein binding	1
protein dimerization activity	1
receptor ligand activity	1
negative chemotaxis	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
lysosome	1
lytic vacuole membrane	1
membrane	1
cell periphery	1
cell-substrate junction	1
apical part of cell	1
plasma membrane region	1
cell leading edge	1
plasma membrane bounded cell projection	1
cytoplasmic vesicle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 27 of 45 annotations. The rest are phylogenetic / computational / electronic (IEA).

27 experimentally-supported GO terms:

GO term	NS	Evidence
T cell activation	BP	direct assay
T cell costimulation	BP	direct assay
endothelial cell migration	BP	direct assay
negative regulation of extracellular matrix disassembly	BP	direct assay
negative regulation of neutrophil chemotaxis	BP	mutant phenotype
positive regulation of cell population proliferation	BP	direct assay
proteolysis	BP	direct assay
regulation of cell-cell adhesion mediated by integrin	BP	direct assay
response to hypoxia	BP	direct assay
apical plasma membrane	CC	direct assay
cell surface	CC	direct assay
endocytic vesicle	CC	direct assay
extracellular exosome	CC	high-throughput assay
focal adhesion	CC	high-throughput assay
lamellipodium	CC	direct assay
lysosomal membrane	CC	high-throughput assay
membrane	CC	high-throughput assay
plasma membrane	CC	direct assay
chemorepellent activity	MF	direct assay
dipeptidyl-peptidase activity	MF	direct assay
identical protein binding	MF	physical interaction
protease binding	MF	physical interaction
protein homodimerization activity	MF	physical interaction
serine-type endopeptidase activity	MF	experiment
serine-type peptidase activity	MF	direct assay
signaling receptor binding	MF	physical interaction
virus receptor activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 3,116 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DPP4	GLP1R	P43220	967
DPP4	GCG	P01275	951
DPP4	PREP	P48147	929
DPP4	GIP	P09681	926
DPP4	SLC5A2	P31639	910
DPP4	INS	P01308	890
DPP4	SI	P14410	882
DPP4	MGAM	O43451	882
DPP4	DPP7	Q9UHL4	866
DPP4	ACE2	Q9BYF1	853
DPP4	ADA	P00813	837
DPP4	ANPEP	P15144	815
DPP4	DNPEP	Q9ULA0	808
DPP4	NAALAD2	Q9Y3Q0	792
DPP4	ACE	P12821	790

IntAct

Human interaction partners of DPP4 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

22 partners by confidence:

Partner	Interaction type	MIscore	Records
S	physical association	0.840	17
CCL11	direct interaction	0.620	2
CXCL10	direct interaction	0.620	2
CXCL11	direct interaction	0.620	2
CXCL2	direct interaction	0.620	2
CXCL9	direct interaction	0.620	2
GRM2	physical association	0.520	2
ADA	direct interaction	0.440	5
GCG	cleavage reaction	0.440	4
CXCL12	direct interaction	0.440	3
VIP	cleavage reaction	0.440	2
ADCYAP1	cleavage reaction	0.440	1
CCL22	cleavage reaction	0.440	1
CCL5	cleavage reaction	0.440	1
GHRH	cleavage reaction	0.440	1
GIP	cleavage reaction	0.440	1
NPPB	cleavage reaction	0.440	1
NPY	cleavage reaction	0.440	1
PYY	cleavage reaction	0.440	1
TAC1	cleavage reaction	0.440	1
TUBGCP2	direct interaction	0.440	1
DKK1	physical association	0.370	1

BioGRID (613 interactions; top human partners by supporting records in a sample of 600 records): ADA (Affinity Capture-Western; 3 records), DUSP26 (Affinity Capture-MS; 3 records), FAP (Affinity Capture-MS; 3 records), ACTB (Affinity Capture-MS; 2 records), ACTBL2 (Affinity Capture-MS; 2 records), ACTC1 (Affinity Capture-MS; 2 records), ACTN1 (Affinity Capture-MS; 2 records), ACTN4 (Affinity Capture-MS; 2 records), AIF1L (Affinity Capture-MS; 2 records), AIMP1 (Affinity Capture-MS; 2 records), ARPC3 (Affinity Capture-MS; 2 records), ATAD3A (Affinity Capture-MS; 2 records), ATAD3B (Affinity Capture-MS; 2 records), ATP1B3 (Affinity Capture-MS; 2 records), ATP5H (Affinity Capture-MS; 2 records)

SIGNOR signaling

7 signaling interactions:

A	Effect	B	Mechanism
GPC3	down-regulates	DPP4	binding
“Sitagliptin phosphate monohydrate”	down-regulates	DPP4	“chemical inhibition”
linagliptin	“down-regulates activity”	DPP4	“chemical inhibition”
vildagliptin	“down-regulates activity”	DPP4	“chemical inhibition”
saxagliptin	“down-regulates activity”	DPP4	“chemical inhibition”
sitagliptin	“down-regulates activity”	DPP4	“chemical inhibition”
alogliptin	“down-regulates activity”	DPP4	“chemical inhibition”

Protein complexes (CORUM) (7)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

7 complexes by size:

Complex	Subunits	Members
★ BCL10-CARD11-DPP4-IKBKB complex	4	BCL10, CARD11, DPP4, IKBKB
★ ADA-ADORA2A-DPP4 complex	3	DPP4, ADA, ADORA2A
★ ADA-DPP4 complex	2	ADA, DPP4
★ DPP4-FAP complex	2	DPP4, FAP
★ DPP4-IGF2R complex	2	DPP4, IGF2R
★ DPP4-GPC3 complex	2	DPP4, GPC3
★ CAV1-DPP4 complex	2	CAV1, DPP4

Ligand–receptor pairs (CellPhoneDB) (7)

Curated ligand–receptor partners (cell-cell communication), distinct from the protein–protein interactions above.

7 ligand–receptor pairs:

Partner	This gene’s role	Signaling class
CCL11	receptor	Signaling by Chemokines
CXCL9	receptor	Signaling by Chemokines
CCL22	receptor	Signaling by Chemokines
CXCL12	receptor	Signaling by Chemokines
CXCL11	receptor	Signaling by Chemokines
CXCL2	receptor	Signaling by Chemokines
CXCL10	receptor	Signaling by Chemokines

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 22 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Glucagon-type ligand receptors	5	86.5×	5e-08
Chemokine receptors bind chemokines	8	74.9×	3e-12
Peptide ligand-binding receptors	6	22.2×	3e-06
G alpha (i) signalling events	10	19.5×	5e-10
G alpha (s) signalling events	5	18.3×	6e-05
GPCR ligand binding	5	16.0×	1e-04
Signaling by GPCR	5	10.0×	8e-04

GO biological processes:

GO term	Partners	Fold	FDR
chemokine-mediated signaling pathway	7	108.0×	7e-11
chemotaxis	8	51.8×	2e-10
adenylate cyclase-activating G protein-coupled receptor signaling pathway	8	43.1×	7e-10
neuropeptide signaling pathway	5	40.9×	7e-06
cell-cell signaling	8	26.5×	3e-08
positive regulation of cell migration	5	14.7×	4e-04
inflammatory response	8	14.4×	3e-06
G protein-coupled receptor signaling pathway	7	12.1×	4e-05

Disease & clinical

Genetic variants

Variant evidence for DPP4: 150 ClinVar records (3 pathogenic / likely pathogenic); 33 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

150 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	2
Uncertain significance	97
Likely benign	10
Benign	6

Top pathogenic / likely-pathogenic (3)

Showing all 3 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
253674	GRCh37/hg19 2q24.2-24.3(chr2:161542325-164640864)x1	Pathogenic	criteria provided, single submitter	1
523687	Single allele	Likely pathogenic	criteria provided, single submitter	1
932936	GRCh37/hg19 2q24.2(chr2:161561653-163178787)	Likely pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore DPP4’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 34 predictions of 2,196):

Position(s)	Effect	Δscore	Sites
2:161995373–161995374	acceptor_loss	1.0000	6
2:162016762	donor_gain	1.0000
2:162016766–162016767	donor_loss	1.0000	5
2:162016867	acceptor_gain	1.0000
2:162016867–162016868	acceptor_loss	1.0000	3
2:162016875	acceptor_gain	1.0000
2:162018727–162018728	donor_loss	1.0000	4
2:162020689–162020690	acceptor_loss	1.0000	6
2:161994965	donor_gain	0.9900
2:161995035–161995036	acceptor_loss	0.9900	6

AlphaMissense

1,648 missense substitutions predicted likely pathogenic (of 5,060 scored), across 437 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D708	8	0.995	0.999
H740	8	0.993	0.998
H704	8	0.976	0.996
D579	8	0.974	0.990
D605	8	0.969	0.992
D200	8	0.962	0.989
H712	8	0.958	0.992
D709	8	0.942	0.986
D737	8	0.937	0.995
N710	8	0.930	0.991
H750	8	0.920	0.961
F713	8	0.903	0.983
D663	8	0.900	0.981
F461	8	0.825	0.958
W201	7	0.993	0.998
W659	7	0.992	0.998
W353	7	0.985	0.996
W62	7	0.984	0.997
E205	7	0.978	0.990
W305	7	0.976	0.995

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Prostate Adenocarcinoma)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

3 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	2.36e-09
Kidney Renal Clear Cell Carcinoma (validation)	favorable	2.32e-05
Prostate Adenocarcinoma (TCGA)	unfavorable	0.000906

Disease associations

OMIM: gene MIM:102720 | disease phenotypes:

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (1 panels, 0 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

1 panels:

Panel	Rating
COVID-19 research	amber

GWAS associations

showing 30 of 33 associations:

Study	Trait	p-value
GCST010698_4	Subcortical volume (min-P)	9e-30
GCST010703_144	Brain morphology (MOSTest)	5e-22
GCST006870_1	Hippocampal tail volume	9e-22
GCST002433_3	Rheumatoid arthritis	2e-21
GCST007327_172	Smoking status (ever vs never smokers)	2e-15
GCST006881_3	Hippocampal tail volume (corrected for total hippocampal volume)	3e-13
GCST006269_946	General cognitive ability	5e-13
GCST006871_1	Total hippocampal volume	5e-13
GCST005316_194	Intelligence (MTAG)	6e-13
GCST008810_51	Smoking initiation (ever regular vs never regular)	2e-12
GCST010702_126	Subcortical volume (MOSTest)	4e-11
GCST006886_2	Subiculum volume	6e-11
GCST005141_52	Cognitive ability (MTAG)	9e-11
GCST006891_1	Dentate gyrus molecular layer volume	2e-10
GCST010043_125	Asthma	2e-9
GCST006268_59	Reaction time	5e-9
GCST005316_127	Intelligence (MTAG)	9e-9
GCST002433_6	Rheumatoid arthritis	1e-8
GCST005316_125	Intelligence (MTAG)	1e-8
GCST010042_111	Asthma	1e-8
GCST010701_119	Cortical surface area (MOSTest)	1e-8
GCST006921_3	Regular attendance at a pub or social club	2e-8
GCST006269_642	General cognitive ability	4e-8
GCST010700_43	Cortical thickness (MOSTest)	4e-8
GCST002539_23	Schizophrenia	5e-8
GCST010699_6	Brain morphology (min-P)	5e-8
GCST004267_2	Blood osmolality (transformed sodium)	7e-8
GCST007277_3	Tourette syndrome	2e-7
GCST009597_16	Multiple sclerosis	2e-7
GCST001485_1	Hippocampal volume	3e-7

EFO canonical traits (from GWAS)

9 canonical traits:

EFO ID	Trait name
EFO:0005035	hippocampal volume
EFO:0004337	intelligence
EFO:0004784	self reported educational attainment
EFO:0008393	reaction time measurement
EFO:0009592	social interaction measurement
EFO:0004318	smoking behavior
EFO:0005670	smoking initiation
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2111469 (SELECTIVITY GROUP), CHEMBL284 (SINGLE PROTEIN)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the DPP4 protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

17 curated-mechanism drugs:

Drug	Modality	Max phase
ALOGLIPTIN BENZOATE	Small molecule	4
ANAGLIPTIN	Small molecule	4
EVOGLIPTIN	Small molecule	4
GOSOGLIPTIN	Small molecule	4
LINAGLIPTIN	Small molecule	4
OMARIGLIPTIN	Small molecule	4
SAXAGLIPTIN HYDROCHLORIDE	Small molecule	4
SITAGLIPTIN FUMARATE	Small molecule	4
TENELIGLIPTIN	Small molecule	4
TRELAGLIPTIN SUCCINATE	Small molecule	4
VILDAGLIPTIN	Small molecule	4
BEGELOMAB	Antibody	3
DBPR-108	Small molecule	3
DUTOGLIPTIN	Small molecule	3
GEMIGLIPTIN	Small molecule	3
BISEGLIPTIN	Small molecule	2
CARMEGLIPTIN	Small molecule	2

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 308,182 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

33 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL376359	ALOGLIPTIN	4	3,917
CHEMBL1929396	ANAGLIPTIN	4	1,153
CHEMBL1779710	EVOGLIPTIN	4	799
CHEMBL515387	GOSOGLIPTIN	4	823
CHEMBL237500	LINAGLIPTIN	4	5,545
CHEMBL2105762	OMARIGLIPTIN	4	1,165
CHEMBL385517	SAXAGLIPTIN ANHYDROUS	4	18,818
CHEMBL1422	SITAGLIPTIN	4	26,952
CHEMBL1201174	SITAGLIPTIN PHOSPHATE	4	269
CHEMBL2147777	TENELIGLIPTIN	4	1,471
CHEMBL1650443	TRELAGLIPTIN	4	1,420
CHEMBL2105754	TRELAGLIPTIN SUCCINATE	4	161
CHEMBL142703	VILDAGLIPTIN	4	20,579
CHEMBL430	GEMIFLOXACIN	4	9,893
CHEMBL1431	METFORMIN	4	169,440
CHEMBL1090	VIDARABINE	4	7,553
CHEMBL1082462	DBPR-108	3	53
CHEMBL4296719	DUTOGLIPTIN	3	1,437
CHEMBL2103745	SAXAGLIPTIN	3	7
CHEMBL145	CAFFEIC ACID	3	36,727
CHEMBL297453	EPIGALOCATECHIN GALLATE	3
CHEMBL50	QUERCETIN	3
CHEMBL165	RESVERATROL	3
CHEMBL4297435	RETAGLIPTIN	3
CHEMBL67279	TALABOSTAT	3
CHEMBL591118	CARMEGLIPTIN	2
CHEMBL4646510	COFROGLIPTIN	2
CHEMBL275638	FLAVONE	2
CHEMBL288114	GALLIC ACID	2
CHEMBL44	GENISTEIN	2
CHEMBL151	LUTEOLIN	2
CHEMBL269277	BETULINIC ACID	1
CHEMBL150	KAEMPFEROL	1

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

4 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs2909451	sitagliptin	PD	Genotype TT is associated with increased activity of DPP4 when treated with sitagliptin as compared to genotypes CC + CT.	PMID:29264572
rs759717	sitagliptin	PD	Genotype CC is associated with increased activity of DPP4 when treated with sitagliptin as compared to genotypes CG + GG.	PMID:29264572
rs2909451	sitagliptin	Efficacy	Genotype TT is associated with decreased response to sitagliptin in people with Diabetes Mellitus, Type 2.	PMID:39792745
rs4664443	sitagliptin	Efficacy	Genotype GG is associated with decreased response to sitagliptin in people with Diabetes Mellitus, Type 2.	PMID:39792745

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — S9: Prolyl oligopeptidase

Most potent curated ligand interactions (18 total), top 18:

Ligand	Action	Affinity	Parameter
begelomab	Binding	10.0	pKd
talabostat	Inhibition	9.74	pKi
teneligliptin	Inhibition	9.43	pIC50
saxagliptin	Inhibition	9.2	pKi
omarigliptin	Inhibition	9.1	pKi
linagliptin	Inhibition	9.0	pKi
compound 24dd [PMID: 20684603]	Inhibition	8.85	pKi
fotagliptin	Inhibition	8.66	pIC50
alogliptin	Inhibition	8.5	pIC50
anagliptin	Inhibition	8.42	pIC50
cofrogliptin	Inhibition	8.38	pIC50
prusogliptin	Inhibition	8.3	pIC50
ZY15557	Competitive	8.26	pKi
sitagliptin	Inhibition	8.1	pIC50
vildagliptin	Inhibition	8.0	pIC50
cetagliptin	Inhibition	7.77	pIC50
compound 1 [Xiao et al. 2014]	Inhibition	6.6	pIC50
compound 9 [PMID: 20718420]	Inhibition	4.7	pIC50

Binding affinities (BindingDB)

4186 measured of 5131 human assays (5270 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
CHEMBL1819091	KI	0.022 nM
CHEMBL5279548	IC50	0.027 nM
8-[(3R)-3-aminopiperidin-1-ium-1-ylidene]-7-but-2-ynyl-1-[(5-fluoro-1,3-benzothiazol-2-yl)methyl]-3-methyl-5H-purine-2,6-dione	IC50	0.05 nM	US-9255098: Xanthine derivative
3-[[8-[(3R)-3-aminopiperidin-1-ium-1-ylidene]-7-but-2-ynyl-3-methyl-2,6-dioxo-5H-purin-1-yl]methyl]pyrazine-2-carbonitrile	IC50	0.08 nM	US-10358449: Xanthine derivative
CHEMBL5269668	IC50	0.09 nM
5-(aminomethyl)-6-(2,4-dichlorophenyl)-2-(3,5-dimethoxyphenyl)pyrimidin-4-amine	IC50	0.1 nM
8-[(3R)-3-aminopiperidin-1-ium-1-ylidene]-1-(1,3-benzothiazol-2-ylmethyl)-7-but-2-ynyl-3-methyl-5H-purine-2,6-dione	IC50	0.1 nM	US-9255098: Xanthine derivative
[6-(2,4-Dichloro-phenyl)-2-(3,5-dimethoxy-phenyl)-5-dimethylaminomethyl-pyrimidin-4-yl]-dimethyl-amine	IC50	0.1 nM
2-[[8-[(3R)-3-aminopiperidin-1-yl]-7-but-2-ynyl-3-methyl-2,6-dioxopurin-1-yl]methyl]-5-chlorobenzoic acid	IC50	0.1 nM	US-20240115577: SMALL MOLECULE REGULATORS OF ALVEOLAR TYPE 2 CELL PROLIFERATION FOR THE TREATMENT OF PULMONARY DISEASES
(S)-1-[(2S,4S)-4-(3-Chloro-4-cyano-phenylamino)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile	IC50	0.13 nM
4-[(3S,5S)-5-((S)-2-Cyano-pyrrolidine-1-carbonyl)-pyrrolidin-3-ylamino]-phthalonitrile	IC50	0.13 nM
CHEMBL5220657	IC50	0.13 nM
CHEMBL5220613	IC50	0.14 nM
CHEMBL5220594	IC50	0.16 nM
5-[(3R,5S)-5-amino-6-(2,5-difluorophenyl)thian-3-yl]-4,6-dihydro-1H-pyrrolo[3,4-d]pyrazole-3-carboxamide	IC50	0.17 nM	US-8853212: Substituted aminotetrahydrothiopyrans and derivatives thereof as dipeptidyl peptidase-IV inhibitors for the treatment of diabetes
N-(3-cyanophenyl)-2-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]acetamide	IC50	0.18 nM	US-10894794: Substituted [1,2,4]triazolo[4,3-a]pyrazines as antidiabetics
(S)-1-[(2S,4S)-4-(4-Nitro-phenylamino)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile	IC50	0.18 nM
CHEMBL4465482	IC50	0.18 nM
(S)-1-[(2S,4S)-4-(4-Cyano-phenylamino)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile	IC50	0.19 nM
1c-meta-F	IC50	0.2 nM
1c-para-F	IC50	0.2 nM
[(2R)-1-[(2S)-2-aminopropanethioyl]pyrrolidin-2-yl]boronic acid	IC50	0.2 nM	US-11559537: Combination therapies using caspase-1 dependent anticancer agents and PGE2 antagonists
8-[(3R)-3-aminopiperidin-1-ium-1-ylidene]-7-but-2-ynyl-1-[(5-chloro-1,3-benzothiazol-2-yl)methyl]-3-methyl-5H-purine-2,6-dione	IC50	0.2 nM	US-9255098: Xanthine derivative
Boronic acid derivative	IC50	0.2 nM	US-11559537: Combination therapies using caspase-1 dependent anticancer agents and PGE2 antagonists
N-((3S)-1-(6-(aminomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carbonyl)pyrrolidin-3-yl)methanesulfonamide	KI	0.2 nM
CHEMBL2147704	IC50	0.2 nM
2-[[8-[(3R)-3-aminopiperidin-1-ium-1-ylidene]-7-but-2-ynyl-3-methyl-2,6-dioxo-5H-purin-1-yl]methyl]-6-fluorobenzonitrile	IC50	0.21 nM	US-10358449: Xanthine derivative
3-chloro-N-[(2S)-1-oxo-1-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]propan-2-yl]benzamide	IC50	0.21 nM	US-10894794: Substituted [1,2,4]triazolo[4,3-a]pyrazines as antidiabetics
N4-(4-chlorobenzyl)-2,4-diaminobutanoylpiperidine	IC50	0.22 nM
(S)-2-Amino-4-[(4-chloro-benzyl)-methyl-amino]-1-piperidin-1-yl-butan-1-one	IC50	0.22 nM
CHEMBL4461587	IC50	0.22 nM
CHEMBL5434074	IC50	0.22 nM
2-(S)-Amino-4-(2-chloro-benzylamino)-1-piperidin-1-yl-butan-1-one	IC50	0.23 nM
6-[(3S,5S)-5-((S)-2-Cyano-pyrrolidine-1-carbonyl)-pyrrolidin-3-ylamino]-nicotinonitrile	IC50	0.25 nM
CHEMBL2147703	IC50	0.26 nM
CHEMBL5219939	IC50	0.26 nM
CHEMBL5220750	IC50	0.27 nM
(S)-1-[(2S,4S)-4-(3,4-Dimethoxy-phenylamino)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile	IC50	0.28 nM
CHEMBL5219299	IC50	0.28 nM
CHEMBL5219451	IC50	0.28 nM
Trifluoro-acetate3-{(R)-4-[4-((S)-1-carboxy-2-methyl-propoxy)-benzylcarbamoyl]-thiazolidin-3-yl}-1-(2,5-difluoro-benzyl)-3-oxo-propyl-ammonium;	IC50	0.3 nM
6-(aminomethyl)-5-(2,4-dichlorophenyl)-N,7-dimethyl-N-(2-(methylsulfonyl)ethyl)imidazo[1,2-a]pyrimidine-2-carboxamide	KI	0.3 nM
(R)-4-((R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl)-3-(tert-butoxymethyl)piperazin-2-one	IC50	0.3 nM	US-20240115577: SMALL MOLECULE REGULATORS OF ALVEOLAR TYPE 2 CELL PROLIFERATION FOR THE TREATMENT OF PULMONARY DISEASES
CHEMBL2063040	IC50	0.3 nM
CHEMBL2147712	IC50	0.3 nM
CHEMBL5267798	IC50	0.3 nM
CHEMBL2147709	IC50	0.32 nM
(S)-1-[(2S,4S)-4-(4-Methoxy-phenylamino)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile	IC50	0.33 nM
(R)-2-((2-(3-Aminopiperidin-1-yl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)methyl)benzonitrile	IC50	0.33 nM
CHEMBL2058971	IC50	0.37 nM

ChEMBL bioactivities

5078 potent at pChembl≥5 of 5391 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.52	Ki	0.03	nM	CHEMBL63860
10.30	IC50	0.05	nM	CHEMBL4113723
10.10	IC50	0.08	nM	CHEMBL4113723
10.10	IC50	0.08	nM	CHEMBL5914058
10.09	Ki	0.082	nM	CHEMBL98869
10.05	IC50	0.09	nM	CHEMBL5269668
10.00	IC50	0.1	nM	CHEMBL34062
10.00	IC50	0.1	nM	CHEMBL186877
10.00	IC50	0.1	nM	LINAGLIPTIN
10.00	IC50	0.1	nM	CHEMBL4111229
10.00	IC50	0.1	nM	CHEMBL4448186
10.00	IC50	0.1	nM	TALABOSTAT
9.92	IC50	0.12	nM	CHEMBL3806052
9.89	IC50	0.13	nM	CHEMBL370046
9.89	IC50	0.13	nM	CHEMBL194717
9.89	IC50	0.13	nM	CHEMBL5220657
9.89	IC50	0.13	nM	CHEMBL456420
9.85	IC50	0.14	nM	CHEMBL3805966
9.85	IC50	0.14	nM	CHEMBL5220613
9.85	IC50	0.14	nM	LINAGLIPTIN
9.82	IC50	0.15	nM	CHEMBL4111229
9.82	IC50	0.15	nM	CHEMBL445437
9.80	IC50	0.16	nM	CHEMBL5220594
9.77	IC50	0.17	nM	CHEMBL3644459
9.75	Kd	0.177	nM	CHEMBL4550812
9.74	IC50	0.18	nM	CHEMBL370540
9.74	Ki	0.18	nM	TALABOSTAT
9.74	IC50	0.18	nM	CHEMBL4465482
9.74	IC50	0.18	nM	CHEMBL1203953
9.74	IC50	0.18	nM	CHEMBL5951803
9.72	IC50	0.19	nM	CHEMBL371143
9.70	IC50	0.2	nM	CHEMBL2147704
9.70	IC50	0.2	nM	CHEMBL4109453
9.70	Ki	0.2	nM	CHEMBL1215018
9.70	IC50	0.2	nM	CHEMBL34842
9.70	IC50	0.2	nM	CHEMBL36666
9.68	IC50	0.21	nM	CHEMBL402163
9.68	IC50	0.21	nM	CHEMBL6057823
9.68	IC50	0.21	nM	LINAGLIPTIN
9.68	IC50	0.21	nM	CHEMBL5870057
9.66	IC50	0.22	nM	CHEMBL4461587
9.66	IC50	0.22	nM	CHEMBL5434074
9.64	IC50	0.23	nM	CHEMBL3805629
9.62	IC50	0.24	nM	CHEMBL3806041
9.60	IC50	0.25	nM	CHEMBL195420
9.59	IC50	0.26	nM	CHEMBL2147703
9.59	IC50	0.26	nM	CHEMBL63860
9.59	IC50	0.26	nM	CHEMBL5219939
9.59	Ki	0.26	nM	CHEMBL1910126
9.57	Ki	0.27	nM	CHEMBL380350

PubChem BioAssay actives

4100 with measured affinity, of 6100 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
Linagliptin	1631907: Binding affinity to human recombinant DPP4 (39 to 766 residues) by surface plasmon resonance analysis	kd	<0.0001	uM
[(2R)-1-[(2S)-2-aminopropanoyl]pyrrolidin-2-yl]boronic acid	287007: Inhibition of human placental DPP4	ki	<0.0001	uM
(2S,3S)-3-amino-2-[4-(4-fluorophenyl)phenyl]-4-[(3S)-3-fluoropyrrolidin-1-yl]-N,N-dimethyl-4-oxobutanamide	393688: Inhibition of DPP4	ic50	<0.0001	uM
4-[[(3S,5S)-5-[(2S)-2-cyanopyrrolidine-1-carbonyl]pyrrolidin-3-yl]amino]benzene-1,2-dicarbonitrile	241057: Inhibitory concentration against human dipeptidylpeptidase IV	ic50	0.0001	uM
(2S)-2-amino-4-[(4-chlorophenyl)methylamino]-1-piperidin-1-ylbutan-1-one	270814: Inhibition of DPP4	ki	0.0001	uM
2-[[8-[(3R)-3-aminopiperidin-1-yl]-7-but-2-ynyl-3-methyl-2,6-dioxopurin-1-yl]methyl]-5-chlorobenzoic acid	1570155: Inhibition of recombinant human DPP4 expressed in baculovirus infected Sf9 insect cells using Gly-Pro-AMC as substrate preincubated for 15 mins followed by substrate addition measured at 60 secs interval for 20 mins by fluorometic method	ic50	0.0001	uM
[(E)-3-ethoxy-3-oxoprop-1-enyl] (2S)-1-[(2S)-2,6-bis[(2-methylpropan-2-yl)oxycarbonylamino]hexanoyl]pyrrolidine-2-carboxylate	1917937: Inhibition of DPP4 (unknown origin) using Gly-Pro-AMC as substrate incubated for 30 mins by fluorescence based enzyme immunoassay	ic50	0.0001	uM
ethenyl (2S)-1-[(2S)-2,6-diaminohexanoyl]pyrrolidine-2-carboxylate	1917937: Inhibition of DPP4 (unknown origin) using Gly-Pro-AMC as substrate incubated for 30 mins by fluorescence based enzyme immunoassay	ic50	0.0001	uM
3-[[8-[(3R)-3-aminopiperidin-1-yl]-7-but-2-ynyl-1-[(2-cyano-3-pyridinyl)methyl]-2,6-dioxo-4,5-dihydropurin-3-yl]methyl]pyridine-2-carbonitrile	1941040: Inhibition of DPP4 (unknown origin) using Gly-Pro-7-amido-4-methylcoumarin as substrate incubated for 30 mins by fluorescence analysis	ic50	0.0001	uM
(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(4,7,8,9,12-pentazatricyclo[6.4.0.02,6]dodeca-1,6,9,11-tetraen-4-yl)oxan-3-amine	1301045: Inhibition of human DPP4	ic50	0.0001	uM
6-(2,4-dichlorophenyl)-2-(3,5-dimethoxyphenyl)-5-[(dimethylamino)methyl]-N,N-dimethylpyrimidin-4-amine	240872: Inhibitory concentration against Dipeptidyl peptidase IV	ic50	0.0001	uM
4-[[(3S)-5-[(2S)-2-cyanopyrrolidine-1-carbonyl]pyrrolidin-3-yl]amino]benzene-1,2-dicarbonitrile	393692: Inhibition of human DPP4	ic50	0.0001	uM
(2S)-1-[(4S)-4-(3-chloro-4-cyanoanilino)pyrrolidine-2-carbonyl]pyrrolidine-2-carbonitrile	393692: Inhibition of human DPP4	ic50	0.0001	uM
5-(aminomethyl)-6-(2,4-dichlorophenyl)-2-(3,5-dimethoxyphenyl)pyrimidin-4-amine	1796753: Fluorogenic Assay from Article 10.1016/j.bmcl.2004.01.019: “Aminomethylpyrimidines as novel DPP-IV inhibitors: a 10(5)-fold activity increase by optimization of aromatic substituents.”	ic50	0.0001	uM
(2S)-1-[(2S,4S)-4-(4-nitroanilino)pyrrolidine-2-carbonyl]pyrrolidine-2-carbonitrile	241057: Inhibitory concentration against human dipeptidylpeptidase IV	ic50	0.0002	uM
5-(aminomethyl)-6-(2,4-dichlorophenyl)-2-(4-fluorophenyl)pyrimidin-4-amine	1796753: Fluorogenic Assay from Article 10.1016/j.bmcl.2004.01.019: “Aminomethylpyrimidines as novel DPP-IV inhibitors: a 10(5)-fold activity increase by optimization of aromatic substituents.”	ic50	0.0002	uM
5-(aminomethyl)-6-(2,4-dichlorophenyl)-2-(3-fluorophenyl)pyrimidin-4-amine	1796753: Fluorogenic Assay from Article 10.1016/j.bmcl.2004.01.019: “Aminomethylpyrimidines as novel DPP-IV inhibitors: a 10(5)-fold activity increase by optimization of aromatic substituents.”	ic50	0.0002	uM
(1S,2R,5S)-5-(11-methyl-1,4,8,10,12-pentazatricyclo[7.3.0.02,6]dodeca-2(6),7,9,11-tetraen-4-yl)-2-(2,4,5-trifluorophenyl)cyclohexan-1-amine	1301045: Inhibition of human DPP4	ic50	0.0002	uM
(1S,2R,5S)-5-(12-cyclopropyl-1,4,8,10,11-pentazatricyclo[7.3.0.02,6]dodeca-2(6),7,9,11-tetraen-4-yl)-2-(2,4,5-trifluorophenyl)cyclohexan-1-amine	1301045: Inhibition of human DPP4	ic50	0.0002	uM
(2S,3R)-2-amino-9-methoxy-3-(2,4,5-trifluorophenyl)-2,3-dihydro-1H-benzo[f]chromene-8-carbonitrile	1638343: Binding affinity to DPP4 (unknown origin) expressed in baculovirus expressing system	kd	0.0002	uM
2-[[8-[(3R)-3-aminopiperidin-1-yl]-7-but-2-ynyl-3-methyl-2,6-dioxopurin-1-yl]methyl]-5-bromobenzoic acid	1570155: Inhibition of recombinant human DPP4 expressed in baculovirus infected Sf9 insect cells using Gly-Pro-AMC as substrate preincubated for 15 mins followed by substrate addition measured at 60 secs interval for 20 mins by fluorometic method	ic50	0.0002	uM
2-[[8-[(3R)-3-aminopiperidin-1-yl]-7-but-2-ynyl-3-methyl-2,6-dioxopurin-1-yl]methyl]-4-chlorobenzoic acid	1570155: Inhibition of recombinant human DPP4 expressed in baculovirus infected Sf9 insect cells using Gly-Pro-AMC as substrate preincubated for 15 mins followed by substrate addition measured at 60 secs interval for 20 mins by fluorometic method	ic50	0.0002	uM
ethenyl (2S)-1-[(2S)-2,6-bis[(2-methylpropan-2-yl)oxycarbonylamino]hexanoyl]pyrrolidine-2-carboxylate	1917937: Inhibition of DPP4 (unknown origin) using Gly-Pro-AMC as substrate incubated for 30 mins by fluorescence based enzyme immunoassay	ic50	0.0002	uM
2-[[2-[(3R)-3-aminopiperidin-1-yl]-4-oxo-6-pyridin-3-ylthieno[3,2-d]pyrimidin-3-yl]methyl]-4-fluorobenzonitrile	2013183: Inhibition of DPP-4 (unknown origin) using Gly-Pro-AMC as substrate preincubated for 10 mins followed by substrate addition measured after 20 mins by fluorescence based assay	ic50	0.0002	uM
(3R)-3-amino-1-[(8R)-8-[(4-fluorophenyl)methyl]-3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one;hydrochloride	312998: Inhibition of DPP4	ic50	0.0002	uM
(2S)-1-[(2S,4S)-4-(4-cyanoanilino)pyrrolidine-2-carbonyl]pyrrolidine-2-carbonitrile	241057: Inhibitory concentration against human dipeptidylpeptidase IV	ic50	0.0002	uM
N-[(3S)-1-[6-(aminomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carbonyl]pyrrolidin-3-yl]methanesulfonamide	499232: Inhibition of human recombinant DPP4 assessed as Gly-Pro-pNA cleavage	ki	0.0002	uM
(2S,3S)-3-[3-(2-chloro-4-methylsulfonylphenyl)-1,2,4-oxadiazol-5-yl]-1-cyclopentylidene-4-cyclopropyl-1-fluorobutan-2-amine;2,2,2-trifluoroacetic acid	322052: Inhibition of human recombinant DPP4 expressed in insect cell	ic50	0.0002	uM
[(2S)-1-[(2S)-2-amino-3-methylbutanoyl]pyrrolidin-2-yl]boronic acid	254910: Inhibitory concentration against human dipeptidylpeptidase 4	ic50	0.0003	uM
saxagliptin anhydrous	1631907: Binding affinity to human recombinant DPP4 (39 to 766 residues) by surface plasmon resonance analysis	kd	0.0003	uM
(2S)-1-[(2S,5R)-5-[(2,4-dichloro-5-nitrophenoxy)methyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonitrile	266034: Inhibition of human recombinant DPP4 by tight-binding assay	ki	0.0003	uM
N-[4-chloro-3-[[(2R,5S)-5-[(2S)-2-cyanopyrrolidine-1-carbonyl]pyrrolidin-2-yl]methoxy]phenyl]-1H-pyrazole-5-carboxamide	266034: Inhibition of human recombinant DPP4 by tight-binding assay	ki	0.0003	uM
N-[5-[(3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)oxan-3-yl]-4,6-dihydro-1H-pyrrolo[3,4-d]pyrazol-3-yl]-1H-imidazole-5-sulfonamide	1262431: Inhibition of recombinant human DPP4 expressed in Sf9 cells using Gly-Pro-AMC substrate after 30 mins by plate reader analysis	ic50	0.0003	uM
2-[3-(aminomethyl)-4-(2,4-dichlorophenyl)-2-methyl-5-oxo-7H-pyrrolo[3,4-b]pyridin-6-yl]-N,N-diethylacetamide	778687: Inhibition of human DPP4 assessed as Gly-Pro-pNA cleavage preincubated for 40 mins followed by substrate addition	ki	0.0003	uM
[(E)-2-phenylethenyl] (2S)-1-[2-[(2-methylpropan-2-yl)oxycarbonylamino]acetyl]pyrrolidine-2-carboxylate	1917937: Inhibition of DPP4 (unknown origin) using Gly-Pro-AMC as substrate incubated for 30 mins by fluorescence based enzyme immunoassay	ic50	0.0003	uM
ethenyl (2S)-1-(2-aminoacetyl)pyrrolidine-2-carboxylate	1917937: Inhibition of DPP4 (unknown origin) using Gly-Pro-AMC as substrate incubated for 30 mins by fluorescence based enzyme immunoassay	ic50	0.0003	uM
[(E)-2-phenylethenyl] (2S)-1-(2-aminoacetyl)pyrrolidine-2-carboxylate	1917937: Inhibition of DPP4 (unknown origin) using Gly-Pro-AMC as substrate incubated for 30 mins by fluorescence based enzyme immunoassay	ic50	0.0003	uM
[(E)-2-phenylethenyl] (2S)-1-[(2S)-2,6-diaminohexanoyl]pyrrolidine-2-carboxylate	1917937: Inhibition of DPP4 (unknown origin) using Gly-Pro-AMC as substrate incubated for 30 mins by fluorescence based enzyme immunoassay	ic50	0.0003	uM
(2S)-2-[4-[[[(4R)-3-[(3R)-3-amino-4-(2,5-difluorophenyl)butanoyl]-1,3-thiazolidine-4-carbonyl]amino]methyl]anilino]-3-methylbutanoic acid	1926211: Inhibition of DPP4 (unknown origin)	ic50	0.0003	uM
(3R)-4-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(pyrazol-1-ylmethyl)-1,4-diazepan-2-one	1797040: Dipeptidyl Peptidase Inhibition Assay from Article 10.1016/j.bmcl.2006.09.099: “(3R)-4-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(2,2,2-trifluoroethyl)-1,4-diazepan-2-one, a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.”	ic50	0.0003	uM
6-[[(3S,5S)-5-[(2S)-2-cyanopyrrolidine-1-carbonyl]pyrrolidin-3-yl]amino]pyridine-3-carbonitrile	241057: Inhibitory concentration against human dipeptidylpeptidase IV	ic50	0.0003	uM
(2S)-1-[(2S,4S)-4-(4-methoxyanilino)pyrrolidine-2-carbonyl]pyrrolidine-2-carbonitrile	241057: Inhibitory concentration against human dipeptidylpeptidase IV	ic50	0.0003	uM
(2S)-1-[(2S,4S)-4-(3,4-dimethoxyanilino)pyrrolidine-2-carbonyl]pyrrolidine-2-carbonitrile	241057: Inhibitory concentration against human dipeptidylpeptidase IV	ic50	0.0003	uM
(3R)-4-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(pyrazin-2-ylmethyl)-1,4-diazepan-2-one	273979: In vitro inhibition of human DPP-4 activity	ic50	0.0003	uM
(3R)-3-amino-1-[3-(trifluoromethyl)-8-[[2-(trifluoromethyl)phenyl]methyl]-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one;hydrochloride	312998: Inhibition of DPP4	ic50	0.0003	uM
(3R)-3-amino-1-[8-[(4-fluorophenyl)-hydroxymethyl]-3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one;hydrochloride	312998: Inhibition of DPP4	ic50	0.0003	uM
6-(aminomethyl)-5-(2,4-dichlorophenyl)-N,7-dimethyl-N-(2-methylsulfonylethyl)imidazo[1,2-a]pyrimidine-2-carboxamide	499232: Inhibition of human recombinant DPP4 assessed as Gly-Pro-pNA cleavage	ki	0.0003	uM
2-[[2-[(3R)-3-aminopiperidin-1-yl]-4-oxothieno[3,2-d]pyrimidin-3-yl]methyl]benzonitrile	567004: Inhibition of DPP4 after 20 mins by fluorescence assay	ic50	0.0003	uM
(2S)-2-[4-[[[(4R)-3-[3-amino-4-(2,5-difluorophenyl)butanoyl]-1,3-thiazolidine-4-carbonyl]amino]methyl]phenoxy]-3-methylbutanoic acid;2,2,2-trifluoroacetic acid	241218: Inhibition of human recombinant Dipeptidylpeptidase IV	ic50	0.0003	uM
[(2R)-1-(2-aminoacetyl)pyrrolidin-2-yl]boronic acid	390968: Inhibition of human placental DPP4	ki	0.0004	uM

CTD chemical–gene interactions

88 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression, increases expression	6
Sitagliptin Phosphate	affects binding, decreases activity	4
Valproic Acid	affects expression, decreases expression, increases expression	4
Progesterone	increases expression, affects cotreatment	3
Cyclosporine	decreases expression	3
nickel sulfate	decreases expression, increases expression	2
entinostat	increases expression, affects cotreatment	2
saxagliptin	decreases activity	2
Arsenic Trioxide	decreases expression	2
Vildagliptin	decreases activity	2
Acetaminophen	increases expression, decreases expression	2
Allergens	affects cotreatment, decreases expression, decreases abundance, increases expression	2
Vehicle Emissions	affects cotreatment, decreases expression, decreases abundance, increases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Doxorubicin	decreases expression, increases cleavage, increases reaction, increases expression, increases response to substance	2
Estradiol	increases expression, affects cotreatment, decreases expression	2
Quercetin	affects cotreatment, decreases expression	2
Smoke	decreases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Particulate Matter	affects cotreatment, decreases abundance, increases expression, decreases expression	2
bisphenol F	increases expression	1
dicrotophos	decreases expression	1
2,4,6-tribromophenol	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
trichostatin A	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1

ChEMBL screening assays

635 unique, capped per target: 584 binding, 41 admet, 10 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL665781	Binding	Selectivity index of compound was determined for human Dipeptidylpeptidase IV to that of Dipeptidyl-peptidase II	Design, synthesis, and SAR of potent and selective dipeptide-derived inhibitors for dipeptidyl peptidases. — *J Med Chem*
CHEMBL3089985	ADMET	Prodrug conversion assessed as dipeptidyl peptidase 4-mediated ACV formation in human serum at 50 uM after 1 hr by HPLC analysis	Novel water-soluble prodrugs of acyclovir cleavable by the dipeptidyl-peptidase IV (DPP IV/CD26) enzyme. — *Eur J Med Chem*
CHEMBL4616458	Functional	Ex-vivo inhibition of DPP4 in plasma of T2D patient assessed as time duration during which DPP4 inhibition rate stays above 80% during phase 2 clinical study	Design, Synthesis, and Evaluation of a Series of Novel Super Long-Acting DPP-4 Inhibitors for the Treatment of Type 2 Diabetes. — *J Med Chem*

Cellosaurus cell lines

6 cell lines: 6 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B8EV	Abcam HCT 116 DPP4 KO	Cancer cell line	Male
CVCL_B9H3	Abcam A-549 DPP4 KO	Cancer cell line	Male
CVCL_D2EV	Abcam MCF-7 DPP4 KO	Cancer cell line	Female
CVCL_D8K8	Ubigene HCT 116 DPP4 KO	Cancer cell line	Male
CVCL_SL16	HAP1 DPP4 (-) 1	Cancer cell line	Male
CVCL_SL17	HAP1 DPP4 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for DPP4 across ~30M SureChEMBL compounds — explore on Sugi Predict.