ERAP1

Summary

ERAP1 (endoplasmic reticulum aminopeptidase 1, HGNC:18173) is a protein-coding gene on chromosome 5q15, encoding Endoplasmic reticulum aminopeptidase 1 (Q9NZ08). Aminopeptidase that plays a central role in peptide trimming, a step required for the generation of most HLA class I-binding peptides.

The protein encoded by this gene is an aminopeptidase involved in trimming HLA class I-binding precursors so that they can be presented on MHC class I molecules. The encoded protein acts as a monomer or as a heterodimer with ERAP2. This protein may also be involved in blood pressure regulation by inactivation of angiotensin II. Three transcript variants encoding two different isoforms have been found for this gene.

Source: NCBI Gene 51752 — RefSeq curated summary.

At a glance

• GWAS associations: 32
• Clinical variants (ClinVar): 349 total — 1 pathogenic
• Phenotypes (HPO): 85
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001040458

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18173
Approved symbol	ERAP1
Name	endoplasmic reticulum aminopeptidase 1
Location	5q15
Locus type	gene with protein product
Status	Approved
Aliases	ARTS-1, A-LAP, PILS-AP, KIAA0525, ERAAP1
Ensembl gene	ENSG00000164307
Ensembl biotype	protein_coding
OMIM	606832
Entrez	51752

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 12 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000296754, ENST00000443439, ENST00000503311, ENST00000503921, ENST00000507154, ENST00000507859, ENST00000508227, ENST00000512852, ENST00000514604, ENST00000853356, ENST00000853357, ENST00000853358, ENST00000853359, ENST00000853360, ENST00000853361

RefSeq mRNA: 4 — MANE Select: NM_001040458 NM_001040458, NM_001198541, NM_001349244, NM_016442

CCDS: CCDS4085, CCDS47250

Canonical transcript exons

ENST00000443439 — 19 exons

Exon	Start	End
ENSE00001083287	96800862	96801000
ENSE00001083288	96795042	96795162
ENSE00001083289	96797175	96797309
ENSE00001083290	96781693	96781854
ENSE00001083295	96781058	96781198
ENSE00001083296	96793803	96793957
ENSE00001083313	96780423	96780504
ENSE00001159910	96803403	96803943
ENSE00001175385	96790512	96790643
ENSE00001641703	96774484	96776551
ENSE00002063037	96807860	96807945
ENSE00002433936	96793400	96793513
ENSE00003507018	96783924	96784080
ENSE00003519249	96792061	96792192
ENSE00003567217	96783051	96783235
ENSE00003611446	96788531	96788685
ENSE00003612154	96790296	96790367
ENSE00003620440	96785788	96785971
ENSE00003622145	96786470	96786549

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 95.53.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.5184 / max 204.3024, expressed in 1817 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
62700	14.3688	1749
62706	2.2076	889
62703	1.0281	712
62707	0.8481	409
62704	0.7749	555
62705	0.7093	421
62709	0.4960	254
62708	0.4440	262
62702	0.3961	160
62699	0.1455	48

Top tissues by expression

299 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	95.53	gold quality
rectum	UBERON:0001052	95.02	gold quality
monocyte	CL:0000576	94.18	gold quality
colonic epithelium	UBERON:0000397	94.15	gold quality
mononuclear cell	CL:0000842	94.12	gold quality
duodenum	UBERON:0002114	93.94	gold quality
leukocyte	CL:0000738	93.85	gold quality
bone marrow cell	CL:0002092	93.51	gold quality
epithelium of nasopharynx	UBERON:0001951	93.31	gold quality
nasopharynx	UBERON:0001728	93.29	gold quality
calcaneal tendon	UBERON:0003701	93.06	gold quality
colonic mucosa	UBERON:0000317	92.20	gold quality
bronchial epithelial cell	CL:0002328	91.90	gold quality
mucosa of sigmoid colon	UBERON:0004993	91.79	gold quality
vermiform appendix	UBERON:0001154	91.61	gold quality
nasal cavity mucosa	UBERON:0001826	91.52	gold quality
stromal cell of endometrium	CL:0002255	91.32	gold quality
tonsil	UBERON:0002372	91.13	gold quality
small intestine	UBERON:0002108	91.11	gold quality
gall bladder	UBERON:0002110	91.04	gold quality
bone marrow	UBERON:0002371	90.76	gold quality
small intestine Peyer’s patch	UBERON:0003454	90.74	gold quality
jejunum	UBERON:0002115	90.68	gold quality
lymph node	UBERON:0000029	90.59	gold quality
nasal cavity epithelium	UBERON:0005384	90.50	gold quality
caecum	UBERON:0001153	90.22	gold quality
palpebral conjunctiva	UBERON:0001812	90.13	gold quality
placenta	UBERON:0001987	90.12	gold quality
adipose tissue	UBERON:0001013	90.00	gold quality
mucosa of paranasal sinus	UBERON:0005030	89.86	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.89

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFKB1, RELA, RUNX1, TP53

miRNA regulators (miRDB)

133 targeting ERAP1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-98-3P	100.00	74.08	3907
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-4775	99.98	75.00	6394
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-8082	99.95	67.27	1170
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-335-3P	99.93	73.36	4958

Literature-anchored findings (GeneRIF, showing 40)

• Association has been confirmed between the Lys528Arg polymorphism of the adipocyte-derived leucine aminopeptidase gene and essential hypertension. (PMID:11857741)
• ARTS-1 has been identified as a novel TNFR1 binding protein that promotes TNFR1 shedding. (PMID:12189246)
• Customizes antigenic peptides presented by MHC I molecules in the ER (PMID:12368856)
• enhances or limits antigen presentation by trimming epitopes to 8-9 residues (PMID:12436110)
• ARTS-1 is required for interleukin-6 receptor shedding. (PMID:12748171)
• type 1 tumor necrosis factor receptor shedding aminopeptidase regulator(ARTS-1) promotes shedding of two cytokine receptor superfamilies, type I cytokine receptor superfamily (interleukin-6Ralpha) and tumor necrosis factor receptor superfamily (TNFR1) (PMID:12748171)
• The ability of ARTS-1 to enhance type II interleukin-1 (IL-1) decoy receptor shedding represents a new mechanism by which IL-1-induced cellular events can be modulated. (PMID:14662887)
• A-LAP may fit the endometrial localization as an antigen-presenting endoplasmic reticulum aminopeptidase (PMID:15314084)
• ERAP1 was unable to remove several N-terminal amino acids that were trimmed efficiently ERAP2. ERAP1 and ERAP2 are both needed for digestion and cellular antigen presentation. (PMID:15908954)
• oxytocinase subfamily of M1 aminopeptidases play important roles in the maintenance of homeostasis including maintenance of normal pregnancy, memory retention, blood pressure regulation and antigen presentation [review] (PMID:16054015)
• ERAP1 is specialized to process precursors transported by transporter associated with antigen processing (TAP) to peptides that can serve as MHC class I epitopes. (PMID:16286653)
• Calcium-dependent ARTS-1-nucleobindin 2 complexes associate with TNFR1 prior to the commitment of TNFR1 to pathways that result in the constitutive release of TNFR1 exosome-like vesicles or the inducible proteolytic cleavage of TNFR1 ectodomains. (PMID:16407280)
• nucleobindin-2-ARTS-1 complexes play an important role in mediating tumor necrosis factor receptor 1 release to the extracellular compartment. (PMID:16407280)
• low and/or imbalanced expression of ERAP1 and probably ERAP2 may cause improper Ag processing and favor tumor escape from immune surveillance (PMID:16585582)
• generation of an HLA-A-associated epitope from tyrosinase is dependent on glycosylation in the ER, and subsequent deglycosylation by peptide-N-glycanase in the cytosol, due to an inability of ER aminopeptidase 1 to efficiently remove N-terminal residues (PMID:17015730)
• Single nucleotide polymorphism in ARTS1 gene is associated with ankylosing spondylitis (PMID:17952073)
• Data show that adipocyte-derived leucine aminopeptidase (A-LAP) plays important roles in the regulation of blood pressure under both the physiological and pathological conditions. (PMID:17999179)
• Results describe the altered expression of endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 in transformed non-lymphoid human tissues. (PMID:18393273)
• This identifies RBMX as an ARTS-1-associated protein that regulates both the constitutive release of TNFR1 exosome-like vesicles and the inducible proteolytic cleavage of TNFR1 ectodomains. (PMID:18445477)
• These results indicate that Gln(181) is critical for the enzymatic activity and substrate specificity of ERAP-1. (PMID:18593381)
• ERAP1 recognizes the full length of its peptide-substrate and not just the N- and C- termini. It is possible that ERAP1 trimming preferences influence the rate of generation and the composition of antigenic peptides in vivo. (PMID:18987748)
• data indicate variation in ERAP1 is an important contributing factor in cervical carcinogenesis, progressive tumor growth & survival; location of ERAP1-127 SNP in peptidase M1 domain of ERAP1 suggests functional consequences of variation at this locus (PMID:19202550)
• The data indicate that an AS disease locus may reside on a specific ERAP1 haplotype, and its effect is not multiplicative with contributions from TAP and LMP genes. (PMID:19404951)
• This is first confirmation in a non-Caucasian population that genetic polymorphisms in ARTS1 are associated with ankylosing spondylitis, implicating common pathogenetic mechanisms in Korean and Caucasian patients with ankylosing spondylitis. (PMID:19414429)
• Results show that one ERAP1 SNP and a haplotype in the ERAP1 and ERAP2 locus are associated with familial ankylosing spondylitis. (PMID:19433412)
• A number of highly significant associations were identified in regulatory sequences which are good candidates for causing susceptibility to AS, possibly by regulating ERAP1 expression. (PMID:19692350)
• ERAP1 is responsible for removing amino- terminal sequences from antigenic precursors in the endoplasmic reticulum, a key determinant of the amount of epitope displayed on the cell surface and the specificity of the immune response to invading pathogens. (PMID:19828632)
• Genetic polymorphisms in ERAP1 are associated with ankylosing spondylitis (AS) in Han Chinese. IL23R is not associated with AS in Chinese. (PMID:19877036)
• single nucleotide polymorphisms in interleukin 23Receptor and ERAP1 (endoplasmic reticulum aminopeptidase 1) genes are associated with susceptibility to ankylosing spondylitis in the Portuguese population (PMID:19917163)
• We confirmed reported associations of ARTS1 gene polymorphisms with ankylosing spondylitis in a Hungarian cohort study. (PMID:20032103)
• Data show the downregulation of MHC class I, ERAP1, and ERAP2 in aggressive NB cells is attributable to a low transcriptional availability of NF-kappaB, possibly due to an unknown suppressor other than MYCN. (PMID:20103633)
• Polymorphisms in ERAP1 associate with susceptibility to human congenital toxoplasmosis. (PMID:20347630)
• The absence or down-regulated expression of ERAP1 is closely related to the metastasis and invasion of lymph node in ovarian carcinoma. (PMID:20367925)
• heterogeneous expression in melanoma cell lines (PMID:20419298)
• The intermediate accumulation properties of ERAP1 and placental leucine aminopeptidase [PLAP] are distinct and epitope dependent, suggesting that these two enzymes may impose different selective pressures on epitope generation. (PMID:20592285)
• The ERAP1 and ERAP2 polymorphisms associated with ankylosing spondylitis (AS) do not influence the serum cytokine receptor levels in patients with AS. (PMID:20595269)
• data suggest that genetic diversity in ERAP1 and ERAP2 has been maintained by balancing selection and that variants in ERAP2 confer resistance to HIV-1 infection possibly via the presentation of a distinctive peptide repertoire to CD8(+) T cells (PMID:20843824)
• ERAP1 variants only influenced psoriasis susceptibility in individuals carrying the HLA-C risk allele. (PMID:20953190)
• This is the first confirmation in a nonwhite population that genetic polymorphisms of rs27037, rs27434, and rs10865331 are associated with ankylosing spondylitis, implicating common pathogenetic mechanisms in Korean and white patients with AS. (PMID:21041274)
• Our study demonstrated that 2 novel single nucleotide polymorphisms in ERAP1 were associated with ankylosing spondylitis in the Han Chinese population (PMID:21078719)

Cross-species orthologs

18 orthologs

Organism	Symbol	Gene ID
danio_rerio	erap1a	ENSDARG00000013024
danio_rerio	erap1b	ENSDARG00000021859
mus_musculus	Erap1	ENSMUSG00000021583
rattus_norvegicus	Erap1	ENSRNOG00000009997
drosophila_melanogaster	CG7653	FBGN0028935
drosophila_melanogaster	CG9806	FBGN0030222
drosophila_melanogaster	CG2111	FBGN0030223
drosophila_melanogaster	CG6071	FBGN0036186
drosophila_melanogaster	CG5849	FBGN0038897
drosophila_melanogaster	CG3502	FBGN0046253
drosophila_melanogaster	CG31233	FBGN0051233
drosophila_melanogaster	CG31343	FBGN0051343
drosophila_melanogaster	CG31445	FBGN0051445
drosophila_melanogaster	SP1029	FBGN0263236
drosophila_melanogaster	CG46339	FBGN0285963
caenorhabditis_elegans	F49B2.6	WBGENE00009865
caenorhabditis_elegans		WBGENE00011587
caenorhabditis_elegans		WBGENE00012776

Paralogs (11): TRHDE (ENSG00000072657), LTA4H (ENSG00000111144), LNPEP (ENSG00000113441), ENPEP (ENSG00000138792), NPEPPS (ENSG00000141279), RNPEPL1 (ENSG00000142327), AOPEP (ENSG00000148120), ERAP2 (ENSG00000164308), ANPEP (ENSG00000166825), LVRN (ENSG00000172901), RNPEP (ENSG00000176393)

Protein

Protein identifiers

Endoplasmic reticulum aminopeptidase 1 — Q9NZ08 (reviewed: Q9NZ08)

Alternative names: ARTS-1, Adipocyte-derived leucine aminopeptidase, Aminopeptidase PILS, Puromycin-insensitive leucyl-specific aminopeptidase, Type 1 tumor necrosis factor receptor shedding aminopeptidase regulator

All UniProt accessions (4): A0A1D5RMR7, D6RAL9, Q9NZ08, H0Y9X5

UniProt curated annotations — full annotation on UniProt →

Function. Aminopeptidase that plays a central role in peptide trimming, a step required for the generation of most HLA class I-binding peptides. Peptide trimming is essential to customize longer precursor peptides to fit them to the correct length required for presentation on MHC class I molecules. Strongly prefers substrates 9-16 residues long. Rapidly degrades 13-mer to a 9-mer and then stops. Preferentially hydrolyzes the residue Leu and peptides with a hydrophobic C-terminus, while it has weak activity toward peptides with charged C-terminus. May play a role in the inactivation of peptide hormones. May be involved in the regulation of blood pressure through the inactivation of angiotensin II and/or the generation of bradykinin in the kidney.

Subunit / interactions. Monomer. May also exist as a heterodimer; with ERAP2. Interacts with RBMX.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Ubiquitous.

Post-translational modifications. N-glycosylated.

Cofactor. Binds 1 zinc ion per subunit.

Induction. By IFNG/IFN-gamma.

Similarity. Belongs to the peptidase M1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NZ08-1	1	yes
Q9NZ08-2	2

RefSeq proteins (4): NP_001035548, NP_001185470, NP_001336173, NP_057526 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001930	Peptidase_M1	Family
IPR014782	Peptidase_M1_dom	Domain
IPR024571	ERAP1-like_C_dom	Domain
IPR027268	Peptidase_M4/M1_CTD_sf	Homologous_superfamily
IPR034016	M1_APN-typ	Family
IPR042097	Aminopeptidase_N-like_N_sf	Homologous_superfamily
IPR045357	Aminopeptidase_N-like_N	Domain
IPR050344	Peptidase_M1_aminopeptidases	Family

Pfam: PF01433, PF11838, PF17900

Enzyme classification (BRENDA):

• EC 3.4.11.1 — leucyl aminopeptidase (BRENDA: 101 organisms, 467 substrates, 423 inhibitors, 209 Km, 161 kcat entries)
• EC 3.4.11.22 — aminopeptidase I (BRENDA: 21 organisms, 179 substrates, 114 inhibitors, 57 Km, 46 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
LEU-GLY	1.5–8.4	10
L-LEU-4-NITROANILIDE	0.035–12.7	9
LEU-4-NITROANILIDE	0.22–8.8	8
L-LEU-7-AMIDO-4-METHYLCOUMARIN	0.012–1.38	7
L-LEUCINE-4-METHYLCOUMARYL-7-AMIDE	0.015–0.35	6
LEUCYL-4-METHYLCOUMARYL-7-AMIDE	0.0131–0.173	6
BETA-CYCLOHEXYL-L-ALANYL-4-METHYLCOUMARYL-7-AMID	0.0011–0.539	5
LEU-P-NITROANILIDE	0.17–0.97	5
LEUCINAMIDE	4.02–17	5
L-ALANINE-4-METHYLCOUMARYL-7-AMIDE	0.054–1.16	4
L-LEU-GLY	1.8–7.2	4
L-LEUCINE-4-NITROANILIDE	0.14–3	4
L-LEUCYL-4-NITROANILIDE	0.0092–1.2825	4
L-LYS-4-NITROANILIDE	0.094–8.9	4
THIONOLEUCINE-4-ANISIDIDE	4–7	4

UniProt features (117 total): helix 38, strand 34, turn 13, sequence variant 10, glycosylation site 5, binding site 5, topological domain 2, disulfide bond 2, sequence conflict 2, chain 1, site 1, splice variant 1, transmembrane region 1, mutagenesis site 1, active site 1

Structure

Experimental structures (PDB)

23 structures.

PDB	Method	Resolution (Å)
9GK6	X-RAY DIFFRACTION	1.33
9GJS	X-RAY DIFFRACTION	1.35
9GKE	X-RAY DIFFRACTION	1.37
9TD7	X-RAY DIFFRACTION	1.37
9TD5	X-RAY DIFFRACTION	1.45
7Z28	X-RAY DIFFRACTION	1.55
9TDA	X-RAY DIFFRACTION	1.55
9TD3	X-RAY DIFFRACTION	1.57
6Q4R	X-RAY DIFFRACTION	1.6
6T6R	X-RAY DIFFRACTION	1.67
6RQX	X-RAY DIFFRACTION	1.68
9GJN	X-RAY DIFFRACTION	1.72
6RYF	X-RAY DIFFRACTION	1.72
9TD4	X-RAY DIFFRACTION	1.73
3RJO	X-RAY DIFFRACTION	2.3
2YD0	X-RAY DIFFRACTION	2.7
5J5E	X-RAY DIFFRACTION	2.8
6MGQ	X-RAY DIFFRACTION	2.92
3MDJ	X-RAY DIFFRACTION	2.95
3QNF	X-RAY DIFFRACTION	3
7MWC	X-RAY DIFFRACTION	3
7MWB	X-RAY DIFFRACTION	3.2
6M8P	X-RAY DIFFRACTION	3.31

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NZ08-F1	92.78	0.90

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 (2): 438 (transition state stabilizer); 354 (proton acceptor)

Ligand- & substrate-binding residues (5): 183; 317–321; 353; 357; 376

Disulfide bonds (2): 404–443, 736–743

Glycosylation sites (5): 70, 154, 414, 760, 901

Mutagenesis-validated functional residues (1):

Position	Phenotype
438	loss of enzyme activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-983170	Antigen Presentation: Folding, assembly and peptide loading of class I MHC

MSigDB gene sets: 452 (showing top): GSE45365_NK_CELL_VS_BCELL_UP, WALLACE_PROSTATE_CANCER_RACE_UP, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_CIRCULATORY_SYSTEM_PROCESS, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOMF_METALLOPEPTIDASE_ACTIVITY, REACTOME_ANTIGEN_PRESENTATION_FOLDING_ASSEMBLY_AND_PEPTIDE_LOADING_OF_CLASS_I_MHC, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GOBP_POSITIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, GOBP_ANTIGEN_PROCESSING_AND_PRESENTATION_OF_PEPTIDE_ANTIGEN, GOBP_PEPTIDE_METABOLIC_PROCESS, VART_KSHV_INFECTION_ANGIOGENIC_MARKERS_UP, GOBP_REGULATION_OF_IMMUNE_RESPONSE

GO Biological Process (14): angiogenesis (GO:0001525), adaptive immune response (GO:0002250), antigen processing and presentation of peptide antigen via MHC class I (GO:0002474), proteolysis (GO:0006508), membrane protein ectodomain proteolysis (GO:0006509), regulation of blood pressure (GO:0008217), response to bacterium (GO:0009617), antigen processing and presentation of endogenous peptide antigen via MHC class I (GO:0019885), peptide catabolic process (GO:0043171), regulation of innate immune response (GO:0045088), fat cell differentiation (GO:0045444), positive regulation of angiogenesis (GO:0045766), immune system process (GO:0002376), peptide antigen assembly with MHC class I protein complex (GO:0002502)

GO Molecular Function (12): endopeptidase activity (GO:0004175), aminopeptidase activity (GO:0004177), interleukin-6 receptor binding (GO:0005138), interleukin-1, type II receptor binding (GO:0005151), metalloexopeptidase activity (GO:0008235), zinc ion binding (GO:0008270), metalloaminopeptidase activity (GO:0070006), protein binding (GO:0005515), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (9): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), endoplasmic reticulum (GO:0005783), endoplasmic reticulum lumen (GO:0005788), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), membrane (GO:0016020), extracellular exosome (GO:0070062), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
antigen processing and presentation of peptide antigen via MHC class I	2
peptidase activity	2
exopeptidase activity	2
cytoplasm	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
immune response	1
antigen processing and presentation of peptide antigen	1
protein metabolic process	1
membrane protein proteolysis	1
blood circulation	1
regulation of biological quality	1
response to other organism	1
antigen processing and presentation of endogenous peptide antigen	1
peptide metabolic process	1
catabolic process	1
regulation of response to biotic stimulus	1
regulation of defense response	1
regulation of response to external stimulus	1
innate immune response	1
regulation of immune response	1
cell differentiation	1
angiogenesis	1
regulation of angiogenesis	1
positive regulation of vasculature development	1
biological_process	1
MHC class I protein complex assembly	1
peptide antigen assembly with MHC protein complex	1
cytokine receptor binding	1
growth factor receptor binding	1
interleukin-1 receptor binding	1
metallopeptidase activity	1
transition metal ion binding	1
aminopeptidase activity	1
metalloexopeptidase activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1

Protein interactions and networks

STRING

1938 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ERAP1	NUCB2	P80303	924
ERAP1	HLA-C	P04222	881
ERAP1	TPP2	P29144	861
ERAP1	HLA-B	P01889	835
ERAP1	TAPBP	O15533	809
ERAP1	IL23R	Q5VWK5	800
ERAP1	ANTXR2	P58335	769
ERAP1	TNF	P01375	728
ERAP1	IFNG	P01579	674
ERAP1	TNIP1	Q15025	660
ERAP1	IL1R2	P27930	639
ERAP1	KLRC4	O43908	628
ERAP1	TNFRSF1A	P19438	623
ERAP1	CAST	P20810	609
ERAP1	TAPBPL	Q9BX59	602

IntAct

68 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
BRCA1	BRCC3	psi-mi:“MI:0914”(association)	0.610
CXCR4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
SLC15A1	METTL15	psi-mi:“MI:0914”(association)	0.530
APLNR	METTL15	psi-mi:“MI:0914”(association)	0.530
DEFA1	MANBA	psi-mi:“MI:0914”(association)	0.530
HLA-B	LTN1	psi-mi:“MI:0914”(association)	0.530
SCGB1D4	EGFR	psi-mi:“MI:0914”(association)	0.530
CCR6	PODXL	psi-mi:“MI:0914”(association)	0.530
OPALIN	BTAF1	psi-mi:“MI:0914”(association)	0.530
ERAP1	ERAP2	psi-mi:“MI:0915”(physical association)	0.460
ERAP1	ERAP2	psi-mi:“MI:0403”(colocalization)	0.460
ERAP1	env	psi-mi:“MI:0570”(protein cleavage)	0.440
CSNK1G2	ERAP1	psi-mi:“MI:0915”(physical association)	0.400
USP20	ERAP1	psi-mi:“MI:0915”(physical association)	0.400
ERAP1	ZMYM3	psi-mi:“MI:0915”(physical association)	0.400
IL6R	ERAP1	psi-mi:“MI:0915”(physical association)	0.400
ROMO1	ERAP1	psi-mi:“MI:0915”(physical association)	0.400
TMEM205	ERAP1	psi-mi:“MI:0915”(physical association)	0.400
	AGPS	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (101): ERAP1 (Affinity Capture-RNA), ERAP1 (Affinity Capture-RNA), ERAP1 (Affinity Capture-RNA), ERAP1 (Affinity Capture-MS), ERAP1 (Affinity Capture-MS), ERAP1 (Affinity Capture-MS), ERAP1 (Affinity Capture-MS), ERAP1 (Affinity Capture-MS), ERAP1 (Affinity Capture-MS), ERAP1 (Affinity Capture-MS), ERAP1 (Affinity Capture-MS), ERAP1 (Affinity Capture-MS), MUL1 (Affinity Capture-MS), TMEM87A (Affinity Capture-MS), APOL2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0B4K692, A5HUI5, B2RQR8, D3UW23, F1N476, O16796, O44857, O95672, P07861, P08049, P08473, P0C1T0, P0DPD6, P0DPD9, P15144, P15145, P15684, P16406, P42891, P42892, P42893, P50123, P97739, Q07075, Q10715, Q10751, Q18673, Q22523, Q32LQ0, Q495T6, Q4PZA2, Q56H28, Q56NL1, Q58DD0, Q5EGZ1, Q5RE69, Q5RFN1, Q61391, Q6Q4G4, Q8IS64

Diamond homologs: A5HUI5, A6NEC2, A6QPT7, D3UW23, M3XFH7, O57579, O93654, O93655, P0DQU2, P15144, P15145, P15541, P15684, P16406, P32454, P37893, P37898, P50123, P55786, P79098, P79143, P79171, P95928, P97449, P97629, Q07075, Q0J2B5, Q0J5V5, Q10736, Q10737, Q10836, Q11010, Q11011, Q2KHK3, Q32LQ0, Q4TT88, Q59KZ1, Q5RFP3, Q6K4E7, Q6P179

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
ERAP1	“down-regulates quantity”	oligopeptide	“chemical modification”
ERAP1	“up-regulates quantity”	“peptide antigen”	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	203
Likely benign	29
Benign	60

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
189336	NM_001750.7(CAST):c.1873del (p.Val625fs)	Pathogenic

SpliceAI

3834 predictions. Top by Δscore:

Variant	Effect	Δscore
5:96762266:A:AG	acceptor_gain	1.0000
5:96762269:A:AG	acceptor_gain	1.0000
5:96765215:TTTCA:T	acceptor_loss	1.0000
5:96765216:TTCA:T	acceptor_loss	1.0000
5:96765217:TCAGC:T	acceptor_loss	1.0000
5:96765218:CAG:C	acceptor_loss	1.0000
5:96765219:A:AG	acceptor_gain	1.0000
5:96765220:G:GA	acceptor_gain	1.0000
5:96765220:GC:G	acceptor_gain	1.0000
5:96765220:GCA:G	acceptor_gain	1.0000
5:96765220:GCAG:G	acceptor_loss	1.0000
5:96765220:GCAGA:G	acceptor_gain	1.0000
5:96765311:G:GT	donor_gain	1.0000
5:96765322:AAAGG:A	donor_loss	1.0000
5:96765323:AAGGT:A	donor_loss	1.0000
5:96765324:AG:A	donor_loss	1.0000
5:96765325:GGTAA:G	donor_loss	1.0000
5:96765327:T:G	donor_loss	1.0000
5:96766048:TATA:T	acceptor_loss	1.0000
5:96766050:TA:T	acceptor_loss	1.0000
5:96766051:A:AG	acceptor_gain	1.0000
5:96766052:G:GG	acceptor_gain	1.0000
5:96766142:ACAGG:A	donor_loss	1.0000
5:96766143:CAGG:C	donor_loss	1.0000
5:96766144:AGGT:A	donor_loss	1.0000
5:96766145:GGTAA:G	donor_loss	1.0000
5:96766146:GTA:G	donor_loss	1.0000
5:96766147:T:A	donor_loss	1.0000
5:96767435:AAGG:A	acceptor_loss	1.0000
5:96767436:A:AG	acceptor_gain	1.0000

AlphaMissense

6251 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:96793481:C:A	W369C	0.999
5:96793481:C:G	W369C	0.999
5:96793483:A:G	W369R	0.999
5:96793483:A:T	W369R	0.999
5:96788640:A:G	W524R	0.998
5:96788640:A:T	W524R	0.998
5:96793918:T:A	E320V	0.998
5:96792082:A:C	F433L	0.997
5:96792082:A:T	F433L	0.997
5:96792084:A:G	F433L	0.997
5:96793471:A:G	W373R	0.997
5:96793471:A:T	W373R	0.997
5:96793502:G:C	N362K	0.997
5:96793502:G:T	N362K	0.997
5:96793506:C:T	G361E	0.997
5:96793513:A:G	W359R	0.997
5:96793513:A:T	W359R	0.997
5:96793906:A:G	L324P	0.997
5:96793917:T:A	E320D	0.997
5:96793917:T:G	E320D	0.997
5:96793920:C:A	M319I	0.997
5:96793920:C:G	M319I	0.997
5:96793920:C:T	M319I	0.997
5:96793460:T:A	E376D	0.996
5:96793460:T:G	E376D	0.996
5:96793497:A:T	V364D	0.996
5:96793506:C:A	G361V	0.996
5:96793507:C:A	G361W	0.996
5:96793808:G:C	H357D	0.996
5:96793820:G:C	H353D	0.996

dbSNP variants (sampled 300 via entrez): RS1000039730 (5:96803695 C>T), RS1000047069 (5:96906128 T>C), RS1000060125 (5:96879390 T>C), RS1000067802 (5:96926552 T>C), RS1000074611 (5:96885581 G>A,T), RS1000115502 (5:96844173 A>G), RS1000117368 (5:96832949 A>G), RS1000145547 (5:96828577 G>A,T), RS1000146343 (5:96885907 G>A,C), RS1000171081 (5:96823256 C>A,T), RS1000172093 (5:96866678 G>A), RS1000203516 (5:96778723 T>A), RS1000211397 (5:96778451 G>A), RS1000215432 (5:96869375 A>G), RS1000224287 (5:96912523 A>G)

Disease associations

OMIM: gene MIM:606832 | disease phenotypes: MIM:616295

GenCC curated gene-disease

Mondo (2): peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome (MONDO:0014574), long QT syndrome (MONDO:0002442)

Orphanet (1): Peeling skin-leukonychia-acral punctate keratoses-cheilitis-knuckle pads syndrome (Orphanet:444138)

HPO phenotypes

85 total (30 of 85 shown, HPO-id order):

HPO	Term
HP:0000031	Epididymitis
HP:0000083	Renal insufficiency
HP:0000099	Glomerulonephritis
HP:0000155	Oral ulcer
HP:0000488	Retinopathy
HP:0000518	Cataract
HP:0000613	Photophobia
HP:0000618	Blindness
HP:0000708	Atypical behavior
HP:0000737	Irritability
HP:0001061	Acne
HP:0001097	Keratoconjunctivitis sicca
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001269	Hemiparesis
HP:0001287	Meningitis
HP:0001288	Gait disturbance
HP:0001289	Confusion
HP:0001347	Hyperreflexia
HP:0001369	Arthritis
HP:0001482	Subcutaneous nodule
HP:0001637	Abnormal myocardium morphology
HP:0001653	Mitral regurgitation
HP:0001658	Myocardial infarction
HP:0001659	Aortic regurgitation
HP:0001701	Pericarditis
HP:0001733	Pancreatitis
HP:0001744	Splenomegaly
HP:0001824	Weight loss
HP:0001945	Fever

GWAS associations

32 associations (top):

Study	Trait	p-value
GCST000432_3	Alcohol dependence	7.000000e-06
GCST000563_5	Ankylosing spondylitis	5.000000e-12
GCST000833_4	Psoriasis	3.000000e-11
GCST001149_11	Ankylosing spondylitis	2.000000e-27
GCST001387_3	Hodgkin’s lymphoma	7.000000e-06
GCST001725_70	Inflammatory bowel disease	6.000000e-13
GCST001804_5	Behcet’s disease	5.000000e-11
GCST001804_6	Behcet’s disease	4.000000e-08
GCST002501_1	Birdshot chorioretinopathy	2.000000e-09
GCST002738_11	Psoriasis	2.000000e-08
GCST002740_65	Inflammatory skin disease	1.000000e-09
GCST002826_1	Urate levels (BMI interaction)	2.000000e-06
GCST002919_2	Colorectal cancer	7.000000e-08
GCST003268_22	Psoriasis vulgaris	1.000000e-07
GCST005527_38	Psoriasis	2.000000e-08
GCST005527_6	Psoriasis	2.000000e-20
GCST005529_20	Ankylosing spondylitis	1.000000e-41
GCST005529_27	Ankylosing spondylitis	6.000000e-14
GCST005529_28	Ankylosing spondylitis	5.000000e-17
GCST005529_38	Ankylosing spondylitis	4.000000e-45
GCST005537_226	Chronic inflammatory diseases (ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis) (pleiotropy)	6.000000e-54
GCST005951_148	Body mass index	4.000000e-09
GCST006585_527	Blood protein levels	0.000000e+00
GCST007267_83	Systolic blood pressure	5.000000e-10
GCST007361_2	Acute anterior uveitis in ankylosing spondylitis	9.000000e-06
GCST007362_1	Acute anterior uveitis (with or without ankylosing spondylitis)	2.000000e-16
GCST007844_13	Ankylosing spondylitis	1.000000e-09
GCST007880_8	Emotional lability in attention deficit hyperactivity disorder	9.000000e-06
GCST007929_50	Medication use (calcium channel blockers)	3.000000e-09
GCST008129_45	Body mass index	3.000000e-17

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004531	urate measurement
EFO:1001494	psoriasis vulgaris
EFO:0006335	systolic blood pressure
EFO:0008475	mood instability measurement
EFO:0009930	Calcium channel blocker use measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3831223 (PROTEIN FAMILY), CHEMBL5939 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 38,758 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL2103847	TOSEDOSTAT	2	328
CHEMBL29292	UBENIMEX	2	38,430

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

4 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs27524	CAST, ERAP1		0.00	0
rs2248374	ERAP1, ERAP2		0.00	0
rs17524572	ERAP1, ERAP2		0.00	0
rs1363907	ERAP1, ERAP2		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — M1: Aminopeptidase N

Most potent curated ligand interactions (3 total), top 3:

Ligand	Action	Affinity	Parameter
compound 2g [PMID: 27390066]	Inhibition	6.28	pKi
compound 17 [PMID: 23916253]	Inhibition	5.59	pIC50
compound 3v [PMID: 27390066]	Inhibition	3.6	pKi

Binding affinities (BindingDB)

1 measured of 1 human assays (1 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL4093454	IC50	27000 nM

ChEMBL bioactivities

262 potent at pChembl≥5 of 402 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.60	IC50	2.512	nM	CHEMBL6148628
8.20	IC50	6.31	nM	CHEMBL6144896
8.20	IC50	6.31	nM	CHEMBL6144145
8.10	IC50	7.943	nM	CHEMBL6103094
7.90	IC50	12.59	nM	CHEMBL6120227
7.90	IC50	12.59	nM	CHEMBL6103131
7.70	IC50	19.95	nM	CHEMBL6141978
7.70	IC50	19.95	nM	CHEMBL6148628
7.48	IC50	33	nM	CHEMBL3416733
7.48	IC50	33	nM	CHEMBL4095882
7.47	IC50	34	nM	CHEMBL4862557
7.37	IC50	43	nM	CHEMBL4101200
7.37	IC50	43	nM	CHEMBL5517929
7.32	IC50	48	nM	CHEMBL3416733
7.32	IC50	48	nM	CHEMBL4099107
7.30	IC50	50.12	nM	CHEMBL6102138
7.30	IC50	50.12	nM	CHEMBL6145606
7.30	IC50	50.12	nM	CHEMBL6078334
7.28	IC50	52	nM	CHEMBL3416733
7.19	IC50	65	nM	CHEMBL4077855
7.15	IC50	71	nM	CHEMBL4103640
7.10	IC50	79.43	nM	CHEMBL6082969
7.01	IC50	98	nM	CHEMBL4104383
7.00	IC50	99	nM	CHEMBL4863142
7.00	IC50	100	nM	CHEMBL6141978
7.00	IC50	100	nM	CHEMBL6144145
6.99	IC50	102	nM	CHEMBL4081073
6.96	IC50	110	nM	CHEMBL448735
6.94	IC50	115	nM	CHEMBL4875461
6.92	IC50	120	nM	CHEMBL4864508
6.90	IC50	126	nM	CHEMBL4069425
6.85	IC50	141.2	nM	CHEMBL4854733
6.85	IC50	140	nM	CHEMBL4854733
6.84	IC50	143	nM	CHEMBL4085707
6.82	IC50	151	nM	CHEMBL4855038
6.81	IC50	155	nM	CHEMBL4099693
6.75	IC50	178	nM	CHEMBL4080145
6.73	IC50	186.2	nM	CHEMBL3416733
6.72	IC50	190	nM	CHEMBL3416733
6.70	IC50	199.5	nM	CHEMBL6078184
6.70	IC50	199.5	nM	CHEMBL6103094
6.70	IC50	199.5	nM	CHEMBL6144896
6.60	IC50	251.2	nM	CHEMBL6101844
6.58	IC50	262	nM	CHEMBL4854530
6.56	IC50	275	nM	CHEMBL4847534
6.49	IC50	323.6	nM	CHEMBL4853049
6.48	IC50	330	nM	CHEMBL4853049
6.47	IC50	340	nM	CHEMBL4097268
6.42	IC50	377	nM	CHEMBL4850551
6.39	IC50	410	nM	CHEMBL4877339

PubChem BioAssay actives

135 with measured affinity, of 423 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
[(2S)-3-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-2-[[3-(4-hydroxyphenyl)-1,2-oxazol-5-yl]methyl]-3-oxopropyl]-[(1R)-1-amino-3-phenylpropyl]phosphinic acid	1469762: Inhibition of ERAP1 (unknown origin) expressed in Hi5 cells by in vitro fluorimetric assay	ic50	0.0330	uM
[(2S)-2-[[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]carbamoyl]-4-methylpentyl]-[(1R)-1-amino-3-phenylpropyl]phosphinic acid	1199904: Inhibition of human recombinant ERAP1 expressed in baculovirus infected Sf9 cells using L-leucine-7-amido-4-methyl coumarin as substrate after 5 to 10 mins by fluorescence assay	ic50	0.0330	uM
1-[[2-(4-chlorophenyl)-5-fluoro-1-benzofuran-7-carbonyl]amino]cyclohexane-1-carboxylic acid	1765766: Inhibition of wild type ERAP1 (unknown origin) using L-Rho-Succ-FKARKF as substrate preincubated for 15 mins followed by substrate addition and measured after 20 mins by flourescence assay	ic50	0.0340	uM
[(2S)-2-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]carbamoyl]pent-4-ynyl]-[(1R)-1-amino-3-phenylpropyl]phosphinic acid	1469762: Inhibition of ERAP1 (unknown origin) expressed in Hi5 cells by in vitro fluorimetric assay	ic50	0.0430	uM
[(2S)-2-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]carbamoyl]but-3-ynyl]-[(1R)-1-amino-3-phenylpropyl]phosphinic acid	2066903: Inhibition of ERAP1 (unknown origin)	ic50	0.0430	uM
[(2S)-3-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-2-[[3-(4-methoxyphenyl)-1,2-oxazol-5-yl]methyl]-3-oxopropyl]-[(1R)-1-amino-3-phenylpropyl]phosphinic acid	1469762: Inhibition of ERAP1 (unknown origin) expressed in Hi5 cells by in vitro fluorimetric assay	ic50	0.0480	uM
[(2S)-3-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-2-[[3-(2-hydroxyphenyl)-1,2-oxazol-5-yl]methyl]-3-oxopropyl]-[(1R)-1-amino-3-phenylpropyl]phosphinic acid	1469762: Inhibition of ERAP1 (unknown origin) expressed in Hi5 cells by in vitro fluorimetric assay	ic50	0.0650	uM
[(2S)-3-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-2-[[3-(4-chlorophenyl)-1,2-oxazol-5-yl]methyl]-3-oxopropyl]-[(1R)-1-amino-3-phenylpropyl]phosphinic acid	1469762: Inhibition of ERAP1 (unknown origin) expressed in Hi5 cells by in vitro fluorimetric assay	ic50	0.0710	uM
[(2S)-3-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-2-[[3-(3-methoxyphenyl)-1,2-oxazol-5-yl]methyl]-3-oxopropyl]-[(1R)-1-amino-3-phenylpropyl]phosphinic acid	1469762: Inhibition of ERAP1 (unknown origin) expressed in Hi5 cells by in vitro fluorimetric assay	ic50	0.0980	uM
1-[[2-(4-chlorophenyl)-5-fluoro-1-benzofuran-7-carbonyl]amino]cyclopentane-1-carboxylic acid	1765766: Inhibition of wild type ERAP1 (unknown origin) using L-Rho-Succ-FKARKF as substrate preincubated for 15 mins followed by substrate addition and measured after 20 mins by flourescence assay	ic50	0.0990	uM
[(2S)-3-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-2-[[3-(2-chlorophenyl)-1,2-oxazol-5-yl]methyl]-3-oxopropyl]-[(1R)-1-amino-3-phenylpropyl]phosphinic acid	1469762: Inhibition of ERAP1 (unknown origin) expressed in Hi5 cells by in vitro fluorimetric assay	ic50	0.1020	uM
(2S)-2-amino-4-methylpentane-1-thiol	2066909: Inhibition of C-terminal Hexa-histidine-tagged human recombinant ERAP1 expressed in Sf9 cells using L-AMC as substrate incubated for 15 mins by Michaelis-Menten analysis	ic50	0.1100	uM
2-[[2-(4-chlorophenyl)-5-fluoro-1-benzofuran-7-carbonyl]amino]-1,3-dihydroindene-2-carboxylic acid	1765766: Inhibition of wild type ERAP1 (unknown origin) using L-Rho-Succ-FKARKF as substrate preincubated for 15 mins followed by substrate addition and measured after 20 mins by flourescence assay	ic50	0.1150	uM
1-[[2-(4-chlorophenyl)-1-benzofuran-7-carbonyl]amino]cyclohexane-1-carboxylic acid	1765766: Inhibition of wild type ERAP1 (unknown origin) using L-Rho-Succ-FKARKF as substrate preincubated for 15 mins followed by substrate addition and measured after 20 mins by flourescence assay	ic50	0.1200	uM
[(2S)-3-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-3-oxo-2-[(3-phenyl-1,2-oxazol-5-yl)methyl]propyl]-[(1R)-1-amino-3-phenylpropyl]phosphinic acid	1469762: Inhibition of ERAP1 (unknown origin) expressed in Hi5 cells by in vitro fluorimetric assay	ic50	0.1260	uM
[(1R)-1-amino-3-phenylpropyl]-[(2S)-2-[[(2S)-3-(1H-indol-3-yl)-1-methoxy-1-oxopropan-2-yl]carbamoyl]-4-methylpentyl]phosphinic acid	1763044: Inhibition of ERAP1 (unknown origin) using L-AMC as substrate	ic50	0.1400	uM
[(2S)-3-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-2-[[3-(3-chlorophenyl)-1,2-oxazol-5-yl]methyl]-3-oxopropyl]-[(1R)-1-amino-3-phenylpropyl]phosphinic acid	1469762: Inhibition of ERAP1 (unknown origin) expressed in Hi5 cells by in vitro fluorimetric assay	ic50	0.1430	uM
1-[[3-bromo-2-(4-chlorophenyl)-1-benzofuran-7-carbonyl]amino]cyclohexane-1-carboxylic acid	1765766: Inhibition of wild type ERAP1 (unknown origin) using L-Rho-Succ-FKARKF as substrate preincubated for 15 mins followed by substrate addition and measured after 20 mins by flourescence assay	ic50	0.1510	uM
[(2S)-2-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]carbamoyl]-4-methylpentyl]-[(1R)-1-amino-3-phenylpropyl]phosphinic acid	1469762: Inhibition of ERAP1 (unknown origin) expressed in Hi5 cells by in vitro fluorimetric assay	ic50	0.1550	uM
[(2S)-3-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-2-[[3-(2-methoxyphenyl)-1,2-oxazol-5-yl]methyl]-3-oxopropyl]-[(1R)-1-amino-3-phenylpropyl]phosphinic acid	1469762: Inhibition of ERAP1 (unknown origin) expressed in Hi5 cells by in vitro fluorimetric assay	ic50	0.1780	uM
(2R)-2-[[2-(4-chlorophenyl)-5-fluoro-1-benzofuran-7-carbonyl]amino]-3-phenylpropanoic acid	1765766: Inhibition of wild type ERAP1 (unknown origin) using L-Rho-Succ-FKARKF as substrate preincubated for 15 mins followed by substrate addition and measured after 20 mins by flourescence assay	ic50	0.2620	uM
2-(4-chlorophenyl)-5-fluoro-N-[2-(2H-tetrazol-5-yl)propan-2-yl]-1-benzofuran-7-carboxamide	1765766: Inhibition of wild type ERAP1 (unknown origin) using L-Rho-Succ-FKARKF as substrate preincubated for 15 mins followed by substrate addition and measured after 20 mins by flourescence assay	ic50	0.2750	uM
[(1R)-1-amino-3-phenylpropyl]-[(2S)-2-[2-(1H-indol-3-yl)ethylcarbamoyl]-4-methylpentyl]phosphinic acid	1763044: Inhibition of ERAP1 (unknown origin) using L-AMC as substrate	ic50	0.3236	uM
[(2S)-2-[[(2S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]carbamoyl]-4-methylpentyl]-[(1R)-1-amino-3-phenylpropyl]phosphinic acid	1469762: Inhibition of ERAP1 (unknown origin) expressed in Hi5 cells by in vitro fluorimetric assay	ic50	0.3400	uM
2-[[2-(4-chlorophenyl)-5-fluoro-1-benzofuran-7-carbonyl]amino]-2-methylbutanoic acid	1765766: Inhibition of wild type ERAP1 (unknown origin) using L-Rho-Succ-FKARKF as substrate preincubated for 15 mins followed by substrate addition and measured after 20 mins by flourescence assay	ic50	0.3770	uM
(2S)-2-[[(2S)-2-[[[(1R)-1-amino-3-phenylpropyl]-hydroxyphosphoryl]methyl]-4-methylpentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	1763044: Inhibition of ERAP1 (unknown origin) using L-AMC as substrate	ic50	0.4100	uM
(2S)-2-[[(2S)-2-[[(2S,3R)-3-amino-2-hydroxy-5-(4-hydroxyphenoxy)pentanoyl]amino]-4-methylpentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	1893371: Inhibition of recombinant ERAP1 (unknown origin) expressed in baculovirus infected Hi-5 insect cells using L-AMC as substrate by flourescence assay	ic50	0.4800	uM
[(1R)-1-amino-3-phenylpropyl]-[(2R)-2-carbamoyl-4-methylpentyl]phosphinic acid	2066903: Inhibition of ERAP1 (unknown origin)	ic50	0.5130	uM
[(1R)-1-amino-3-phenylpropyl]-[(2S)-2-carbamoyl-4-methylpentyl]phosphinic acid	1314016: Inhibition of recombinant human ERAP1 using L-AMC as substrate measured for 15 to 30 mins by fluorescence analysis	ic50	0.5200	uM
2-[[[1-amino-3-(4-nitrophenyl)propyl]-hydroxyphosphoryl]methyl]-3-phenylpropanoic acid	1314018: Inhibition of human ERAP1 preincubated for 30 to 60 mins followed by addition of Leu-AMC as substrate measured for 15 mins by spectrofluorimetric method	ki	0.5300	uM
methyl (2S)-2-[[(2S)-2-[[(2S,3R)-3-amino-2-hydroxy-5-(4-hydroxyphenoxy)pentanoyl]amino]-4-methylpentanoyl]amino]-3-(1H-indol-3-yl)propanoate	1893371: Inhibition of recombinant ERAP1 (unknown origin) expressed in baculovirus infected Hi-5 insect cells using L-AMC as substrate by flourescence assay	ic50	0.5900	uM
methyl (2S)-2-[[(2S)-2-[[(2S,3R)-3-amino-2-hydroxy-4-(3,4,5-trifluorophenoxy)butanoyl]amino]-4-methylpentanoyl]amino]-3-(1H-indol-3-yl)propanoate	1893371: Inhibition of recombinant ERAP1 (unknown origin) expressed in baculovirus infected Hi-5 insect cells using L-AMC as substrate by flourescence assay	ic50	0.6700	uM
[(2S)-2-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]carbamoyl]-4-methylpentyl]-[(1R)-1-amino-3-phenylpropyl]phosphinic acid	1469762: Inhibition of ERAP1 (unknown origin) expressed in Hi5 cells by in vitro fluorimetric assay	ic50	0.6820	uM
2-[[2-(4-chlorophenyl)-5-fluoro-1-benzofuran-7-carbonyl]amino]-2-methylpropanoic acid	1765766: Inhibition of wild type ERAP1 (unknown origin) using L-Rho-Succ-FKARKF as substrate preincubated for 15 mins followed by substrate addition and measured after 20 mins by flourescence assay	ic50	0.6980	uM
[(2S)-2-(1-adamantylmethyl)-3-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-3-oxopropyl]-[(1R)-1-amino-3-phenylpropyl]phosphinic acid	1469762: Inhibition of ERAP1 (unknown origin) expressed in Hi5 cells by in vitro fluorimetric assay	ic50	0.7260	uM
(2S)-2-[[3-amino-4-[[(2S)-2-amino-4-(4-hydroxyphenyl)butanoyl]amino]benzoyl]amino]-3-(1H-indol-3-yl)propanoic acid	1199904: Inhibition of human recombinant ERAP1 expressed in baculovirus infected Sf9 cells using L-leucine-7-amido-4-methyl coumarin as substrate after 5 to 10 mins by fluorescence assay	ic50	0.8000	uM
benzyl (2S)-2-[[4-amino-3-[[(2S)-2-aminohexanoyl]amino]benzoyl]amino]-3-(1H-indol-3-yl)propanoate	1199904: Inhibition of human recombinant ERAP1 expressed in baculovirus infected Sf9 cells using L-leucine-7-amido-4-methyl coumarin as substrate after 5 to 10 mins by fluorescence assay	ic50	0.9200	uM
[(1R)-1-amino-3-phenylpropyl]-[(2S)-2-[(2S)-2-carbamoylpyrrolidine-1-carbonyl]-4-methylpentyl]phosphinic acid	1469762: Inhibition of ERAP1 (unknown origin) expressed in Hi5 cells by in vitro fluorimetric assay	ic50	0.9490	uM
2-[[[1-amino-3-[4-(hydroxymethyl)phenyl]propyl]-hydroxyphosphoryl]methyl]-3-phenylpropanoic acid	1314018: Inhibition of human ERAP1 preincubated for 30 to 60 mins followed by addition of Leu-AMC as substrate measured for 15 mins by spectrofluorimetric method	ki	0.9910	uM
(4aR,5S,6R,8S,8aR)-5-[2-(furan-3-yl)ethyl]-8-hydroxy-5,6,8a-trimethyl-3,4,4a,6,7,8-hexahydronaphthalene-1-carboxylic acid;azane	1561140: Activation of full length C-terminal His6-tagged ERAP1 (unknown origin)-mediated fluorogenic Leu-AMC substrate hydrolysis after 60 mins by Rapidfire-MS analysis	ic50	1.0000	uM
methyl (2S)-2-[[(2S)-2-[[(2S,3R)-3-amino-2-hydroxy-5-(4-hydroxyphenoxy)pentanoyl]amino]-4-methylpentanoyl]amino]-3-(4-hydroxyphenyl)propanoate	1893371: Inhibition of recombinant ERAP1 (unknown origin) expressed in baculovirus infected Hi-5 insect cells using L-AMC as substrate by flourescence assay	ic50	1.0000	uM
4-methoxy-3-[[2-piperidin-1-yl-5-(trifluoromethyl)phenyl]sulfamoyl]benzoic acid	1581822: Inhibition of ERAP1 in human HeLa cells stably expressing H-2 Kb infected with vaccinia virus containing ss-LEQLE-SIINFEKL epitope assessed as suppression of ss-LEQLE-SIINFEKL binding to MHC1 H-2 Kb at cell surface by measuring reduction in 25D1 staining measured after 16 to 24 hrs by flow cytometric method	ic50	1.0000	uM
2-[[2-(4-chlorophenyl)-1-benzofuran-7-carbonyl]amino]-2-methylpropanoic acid	1765766: Inhibition of wild type ERAP1 (unknown origin) using L-Rho-Succ-FKARKF as substrate preincubated for 15 mins followed by substrate addition and measured after 20 mins by flourescence assay	ic50	1.0270	uM
benzyl (2S)-2-[[3-amino-4-[[(2S)-2-amino-3-(4-phenylmethoxyphenyl)propanoyl]amino]benzoyl]amino]-3-(1H-indol-3-yl)propanoate	1199904: Inhibition of human recombinant ERAP1 expressed in baculovirus infected Sf9 cells using L-leucine-7-amido-4-methyl coumarin as substrate after 5 to 10 mins by fluorescence assay	ic50	1.1000	uM
methyl (2S)-2-[[(2S)-2-[[(2S,3R)-3-amino-2-hydroxy-4-(4-hydroxyphenoxy)butanoyl]amino]-4-methylpentanoyl]amino]-3-(1H-indol-3-yl)propanoate	1893371: Inhibition of recombinant ERAP1 (unknown origin) expressed in baculovirus infected Hi-5 insect cells using L-AMC as substrate by flourescence assay	ic50	1.1000	uM
1-[[2-(4-chlorophenyl)-5-fluoro-1-benzofuran-7-carbonyl]amino]cyclopropane-1-carboxylic acid	1765766: Inhibition of wild type ERAP1 (unknown origin) using L-Rho-Succ-FKARKF as substrate preincubated for 15 mins followed by substrate addition and measured after 20 mins by flourescence assay	ic50	1.1190	uM
(2S)-2-[[4-amino-3-[[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]benzoyl]amino]-3-(1H-indol-3-yl)propanoic acid	1199904: Inhibition of human recombinant ERAP1 expressed in baculovirus infected Sf9 cells using L-leucine-7-amido-4-methyl coumarin as substrate after 5 to 10 mins by fluorescence assay	ic50	1.2000	uM
methyl (2S)-2-[[(2S)-2-[[(2S,3R)-3-amino-2,7-dihydroxyheptanoyl]amino]-4-methylpentanoyl]amino]-3-(4-hydroxyphenyl)propanoate	1893371: Inhibition of recombinant ERAP1 (unknown origin) expressed in baculovirus infected Hi-5 insect cells using L-AMC as substrate by flourescence assay	ic50	1.2000	uM
2-[[4-(aminomethyl)phenyl]methyl]-3-[(1-amino-3-pyridin-4-ylpropyl)-hydroxyphosphoryl]propanoic acid	1314018: Inhibition of human ERAP1 preincubated for 30 to 60 mins followed by addition of Leu-AMC as substrate measured for 15 mins by spectrofluorimetric method	ki	1.5200	uM
7-amino-1-bromo-4-phenyl-5,7,8,9-tetrahydrobenzo[7]annulen-6-one	2066906: Inhibition of human recombinant ERAP1 expressed in baculovirus infected sf9 cells using L-AMC as substrate incubated for 5 to 10 mins by Michaelis-Menten analysis	ic50	1.6000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, affects expression, decreases expression	7
trichostatin A	affects cotreatment, decreases expression	3
sodium arsenite	decreases expression	2
mercuric bromide	decreases expression, affects cotreatment	2
entinostat	decreases expression, increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Cyclosporine	increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
sotorasib	affects cotreatment, increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
cobaltous chloride	increases secretion	1
butyraldehyde	decreases expression	1
potassium chromate(VI)	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, affects expression	1
nutlin 3	affects cotreatment, increases expression	1
bisphenol B	increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression, affects expression	1
jinfukang	affects cotreatment, increases expression	1
NSC 689534	affects binding, increases expression	1
trametinib	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1

ChEMBL screening assays

88 unique, capped per target: 85 binding, 2 functional, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4334276	ADMET	Stability in pH 2 HCl assessed as aminopeptidase (unknown origin)-mediated compound hydrolysis by measuring parent compound remaining at 200 uM up to 6 hrs by RP-HPLC analysis	Astratides: Insulin-Modulating, Insecticidal, and Antifungal Cysteine-Rich Peptides from Astragalus membranaceus. — J Nat Prod
CHEMBL1041814	Binding	Inhibition of PILS at 10 uM	Discovery of 4-[(2S)-2-{[4-(4-chlorophenoxy)phenoxy]methyl}-1-pyrrolidinyl]butanoic acid (DG-051) as a novel leukotriene A4 hydrolase inhibitor of leukotriene B4 biosynthesis. — J Med Chem
CHEMBL3562016	Functional	PubChem BioAssay. MLPCN ERAP1 Measured in Biochemical System Using Plate Reader - 7016-01_Inhibitor_Dose_DryPowder_Activity_Set2. (Class of assay: confirmatory)	PubChem BioAssay data set

Cellosaurus cell lines

10 cell lines: 7 cancer cell line, 3 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B7X6	Abcam Raji ERAP1 KO	Cancer cell line	Male
CVCL_B9XT	Abcam THP-1 ERAP1 KO	Cancer cell line	Male
CVCL_C6ZN	Abcam PC-3 ERAP1 KO	Cancer cell line	Male
CVCL_D7GD	Ubigene HEK293T ERAP1 KO	Transformed cell line	Female
CVCL_E1KA	HyCyte HEK293T KO-hERAP1	Transformed cell line	Female
CVCL_E1LN	HyCyte K-562 KO-hERAP1	Cancer cell line	Female
CVCL_E1WA	HAP1 ERAP1 (-) 2	Cancer cell line	Male
CVCL_E1WB	HAP1 ERAP1 (-) 3	Cancer cell line	Male
CVCL_UE98	BCH-30	Transformed cell line	Sex unspecified
CVCL_XN50	HAP1 ERAP1 (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

66 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02513940	PHASE4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	PHASE4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	PHASE4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
NCT01648205	PHASE2	COMPLETED	Long-term Efficacy Study of Sodium Channel Blocker in LQT3 Patients
NCT02412709	PHASE2	UNKNOWN	Long QT Syndrome Screening in Newborns
NCT04581408	PHASE2	COMPLETED	Mutation-specific Therapy for the Long QT Syndrome
NCT00316459	PHASE1	COMPLETED	Study Evaluating the Effects of Multiple Oral Doses of ERB-041 on Cardiac Repolarization in Healthy Subjects
NCT01849003	PHASE1	COMPLETED	Study of the Effect of GS-6615 in Subjects With LQT-3
NCT02365532	PHASE1	COMPLETED	Effect of Oral GS-6615 on Dofetilide-Induced QT Prolongation, Safety, and Tolerability in Healthy Adults
NCT02412098	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Hepatic Function
NCT02441829	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Renal Function
NCT05759962	PHASE1	COMPLETED	Phase 1 Study of LQT-1213 in Healthy Adults
NCT05906732	PHASE1/PHASE2	TERMINATED	Study of LQT-1213 on QTc-induced Prolongation in Healthy Adult Subjects (Part1) and on Congenital Long QT in Patients Diagnosed With Type 2 or 3 Long QT Syndrome (Part 2).
NCT00005176	Not specified	COMPLETED	Long QT Syndrome-Population Genetics and Cardiac Studies
NCT00005250	Not specified	COMPLETED	Linkage Study of Long QT Syndrome In An Amish Kindred
NCT00005367	Not specified	COMPLETED	Epidemiology of Long QTand Asian Sudden Death in Sleep
NCT00221832	Not specified	UNKNOWN	Molecular Genetic Screening and Identification of Congenital Arrhythmogenic Diseases
NCT00292032	Not specified	COMPLETED	Registry of Unexplained Cardiac Arrest
NCT00335036	Not specified	TERMINATED	Pediatric Lead Extractability and Survival Evaluation (PLEASE)
NCT00399412	Not specified	COMPLETED	ECG Signal Collection From Long QT Syndrome, Wide QRS Complexes, Heart Failure, and Cardiac Resynchronization Patients
NCT00488254	Not specified	COMPLETED	The Long QT Syndrome in Pregnancy
NCT00588965	Not specified	COMPLETED	Effect of Beta-blocker Therapy on QTc Response in Exercise and Recovery in Normal Subjects
NCT01705925	Not specified	COMPLETED	Multicenter Evaluation of Children and Young Adults With Genotype Positive Long QT Syndrome
NCT01903564	Not specified	COMPLETED	Fetal and Neonatal Magnetophysiology
NCT02082431	Not specified	COMPLETED	Determine the Incidence of Long QT Amongst a Large Cohort of Subjects Diagnosed With Unilateral or Bilateral Sensorineural Hearing Loss.
NCT02413450	Not specified	ENROLLING_BY_INVITATION	Derivation of Human Induced Pluripotent Stem (iPS) Cells to Heritable Cardiac Arrhythmias
NCT02425189	Not specified	COMPLETED	The Canadian National Long QT Syndrome Registry
NCT02439645	Not specified	TERMINATED	A Registry to Determine the Clinical and Genetic Risk Factors for Torsade De Pointes
NCT02439658	Not specified	UNKNOWN	Genetics of QT Prolongation With Antiarrhythmics
NCT02549664	Not specified	COMPLETED	Exercise in Genetic Cardiovascular Conditions
NCT02581241	Not specified	COMPLETED	Abnormal QT-Response to the Sudden Tachycardia Provoked by Standing in Individuals With Drug-induced Long QT Syndrome
NCT02680080	Not specified	COMPLETED	Effect of Grapefruit on QT Interval in Healthy Volunteers and Patients With Congenital Long QT Syndrome
NCT02775513	Not specified	UNKNOWN	Metabolism of Patients With Genetically Caused Cardiac Arrhythmia
NCT02814981	Not specified	UNKNOWN	Hydroxyzine and Risk of Prolongation of QT Interval
NCT02876380	Not specified	COMPLETED	Prospective Identification of Long QT Syndrome in Fetal Life
NCT03182777	Not specified	COMPLETED	Safety of Local Dental Anesthesia in Patients With Cardiac Channelopathies
NCT03544918	Not specified	COMPLETED	Prevalence of Congenital Long QT Syndrome and Acquired QT Prolongation in a Hospital Cohort
NCT03642405	Not specified	UNKNOWN	Drug-induced Repolarization ECG Changes
NCT03678311	Not specified	COMPLETED	Long QT Syndrome and Sleep Apnea