PSMD3

Summary

PSMD3 (proteasome 26S subunit, non-ATPase 3, HGNC:9560) is a protein-coding gene on chromosome 17q21.1, encoding 26S proteasome non-ATPase regulatory subunit 3 (O43242). Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. It is a common-essential gene (DepMap: required in 100.0% of cancer cell lines).

The 26S proteasome is a multicatalytic proteinase complex with a highly ordered structure composed of 2 complexes, a 20S core and a 19S regulator. The 20S core is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. The 19S regulator is composed of a base, which contains 6 ATPase subunits and 2 non-ATPase subunits, and a lid, which contains up to 10 non-ATPase subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. This gene encodes a member of the proteasome subunit S3 family that functions as one of the non-ATPase subunits of the 19S regulator lid. Single nucleotide polymorphisms in this gene are associated with neutrophil count.

Source: NCBI Gene 5709 — RefSeq curated summary.

At a glance

• GWAS associations: 30 (top 4% of genes corpus-wide)
• Clinical variants (ClinVar): 74 total — 1 likely-pathogenic
• GTEx eGene: eQTL in 18 tissues, sQTL in 13 (q < 0.05)
• ChEMBL bioactivity: 2 clinical-phase molecules tested; no curated mechanism-of-action drug
• Cancer dependency (DepMap): dependent in 100.0% of screened cell lines (common-essential)
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.17 (highly constrained)
• MANE Select transcript: NM_002809
• Interaction hub: 2,326 STRING partners (top 5% of genes corpus-wide)
• Notable: 74 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9560
Approved symbol	PSMD3
Name	proteasome 26S subunit, non-ATPase 3
Location	17q21.1
Locus type	gene with protein product
Status	Approved
Aliases	S3, P58, Rpn3
Ensembl gene	ENSG00000108344
Ensembl biotype	protein_coding
OMIM	617676
Entrez	5709

Gene structure

Transcript identifiers

Ensembl transcripts: 29 — 16 protein_coding, 11 nonsense_mediated_decay, 2 retained_intron

MANE Select: ENST00000264639

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

ENST00000264639, ENST00000415039, ENST00000485835, ENST00000540504, ENST00000580980, ENST00000871888, ENST00000871889, ENST00000871890, ENST00000871891, ENST00000916285, ENST00000916286, ENST00000916287, ENST00000916288, ENST00000916289, ENST00000916290, ENST00000998350, ENST00000998351, ENST00000998352, ENST00000998353, ENST00001046746, ENST00001046747, ENST00001046748, ENST00001081765, ENST00001081766, ENST00001081767, ENST00001081768, ENST00001081769, ENST00001123747, ENST00001140804

RefSeq mRNA: 1 — MANE Select: NM_002809 NM_002809

CCDS: CCDS11356

Canonical transcript exons

ENST00000264639 — 12 exons

Exon	Start	End
ENSE00001388354	39997504	39997959
ENSE00001410218	39980807	39981190
ENSE00001729071	39984294	39984484
ENSE00003470448	39997330	39997380
ENSE00003496437	39986575	39986712
ENSE00003496673	39989739	39989929
ENSE00003520326	39995424	39995527
ENSE00003531197	39995176	39995295
ENSE00003533949	39994954	39995068
ENSE00003565435	39990094	39990197
ENSE00003574285	39988683	39988819
ENSE00003628239	39996183	39996338

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 98.18.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 126.3006 / max 836.0630, expressed in 1828 samples.

Highest expression (Bgee): gastrocnemius, muscle of leg, hindlimb stylopod muscle, skin of leg, cortical plate.

Genetic regulation across tissues (GTEx eQTL / sQTL)

PSMD3 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 18 tissues and its splicing (sQTL) in 13 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 31 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Muscle Skeletal	sqtl	1.4e-22	-0.41	17:39991041:C:T
Artery Tibial	sqtl	5.0e-09	-0.31	17:39973588:T:A
Esophagus Mucosa	eqtl	2.2e-07	-0.08	17:40003082:T:C
Cells Cultured fibroblasts	eqtl	2.5e-07	-0.06	17:39979773:G:T
Nerve Tibial	sqtl	3.1e-06	-0.33	17:40024880:C:T
Testis	eqtl	6.5e-06	-0.21	17:39999545:G:A
Nerve Tibial	eqtl	4.0e-05	+0.09	17:40032802:A:G
Esophagus Muscularis	sqtl	6.0e-05	-0.32	17:39990289:C:G
Artery Aorta	sqtl	1.5e-04	-0.26	17:39979773:G:T
Colon Sigmoid	sqtl	1.7e-04	-0.22	17:39984674:A:C
Muscle Skeletal	eqtl	2.3e-04	+0.07	17:40007683:C:T
Skin Not Sun Exposed Suprapubic	eqtl	2.6e-04	-0.15	17:39971460:A:G
Esophagus Gastroesophageal Junction	sqtl	3.1e-04	-0.32	17:40005254:T:C
Breast Mammary Tissue	eqtl	3.9e-04	+0.66	17:39982781:G:A
Brain Cerebellum	eqtl	5.6e-04	-0.15	17:40007397:T:C
Whole Blood	eqtl	7.2e-04	-0.17	17:39971460:A:G
Artery Tibial	eqtl	7.7e-04	-0.13	17:39983981:C:G
Lung	eqtl	8.9e-04	-0.14	17:39987722:G:A
Brain Cerebellar Hemisphere	eqtl	1.7e-03	-0.29	17:39980309:T:G
Adipose Visceral Omentum	sqtl	1.7e-03	-0.24	17:39973588:T:A

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
160654	102.4532	1827
160653	23.8474	1815

Top tissues by expression

showing 100 of 297 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
gastrocnemius	UBERON:0001388	98.18	gold quality
muscle of leg	UBERON:0001383	97.62	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.35	gold quality
skin of leg	UBERON:0001511	97.05	gold quality
cortical plate	UBERON:0005343	96.83	gold quality
mucosa of transverse colon	UBERON:0004991	96.80	gold quality
skin of abdomen	UBERON:0001416	96.60	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.58	gold quality
stromal cell of endometrium	CL:0002255	96.53	gold quality
ganglionic eminence	UBERON:0004023	96.48	gold quality
body of uterus	UBERON:0009853	96.28	gold quality
cerebellar hemisphere	UBERON:0002245	96.23	gold quality
cerebellar cortex	UBERON:0002129	96.18	gold quality
mucosa of stomach	UBERON:0001199	96.15	gold quality
ectocervix	UBERON:0012249	96.12	gold quality
apex of heart	UBERON:0002098	96.05	gold quality
left uterine tube	UBERON:0001303	95.99	gold quality
transverse colon	UBERON:0001157	95.96	gold quality
right frontal lobe	UBERON:0002810	95.93	gold quality
muscle organ	UBERON:0001630	95.91	gold quality
endocervix	UBERON:0000458	95.90	gold quality
right lobe of liver	UBERON:0001114	95.90	gold quality
ventricular zone	UBERON:0003053	95.90	gold quality
right ovary	UBERON:0002118	95.83	gold quality
left adrenal gland	UBERON:0001234	95.80	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	95.80	gold quality
left ovary	UBERON:0002119	95.68	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.68	gold quality
right adrenal gland	UBERON:0001233	95.67	gold quality
lower esophagus	UBERON:0013473	95.67	gold quality
muscle layer of sigmoid colon	UBERON:0035805	95.67	gold quality
left adrenal gland cortex	UBERON:0035825	95.61	gold quality
right atrium auricular region	UBERON:0006631	95.60	gold quality
prefrontal cortex	UBERON:0000451	95.52	gold quality
right adrenal gland cortex	UBERON:0035827	95.51	gold quality
adenohypophysis	UBERON:0002196	95.42	gold quality
popliteal artery	UBERON:0002250	95.41	gold quality
tibial artery	UBERON:0007610	95.41	gold quality
tibial nerve	UBERON:0001323	95.40	gold quality
left testis	UBERON:0004533	95.30	gold quality
minor salivary gland	UBERON:0001830	95.28	gold quality
upper lobe of left lung	UBERON:0008952	95.23	gold quality
cerebellum	UBERON:0002037	95.21	gold quality
body of stomach	UBERON:0001161	95.19	gold quality
adrenal cortex	UBERON:0001235	95.18	gold quality
heart left ventricle	UBERON:0002084	95.18	gold quality
left lobe of thyroid gland	UBERON:0001120	95.09	gold quality
cardiac atrium	UBERON:0002081	95.09	gold quality
islet of Langerhans	UBERON:0000006	95.08	gold quality
right testis	UBERON:0004534	95.07	gold quality
esophagus	UBERON:0001043	95.05	gold quality
right lobe of thyroid gland	UBERON:0001119	95.03	gold quality
right coronary artery	UBERON:0001625	95.03	gold quality
aorta	UBERON:0000947	95.01	gold quality
cardiac ventricle	UBERON:0002082	94.99	gold quality
rectum	UBERON:0001052	94.98	gold quality
metanephros cortex	UBERON:0010533	94.94	gold quality
left coronary artery	UBERON:0001626	94.90	gold quality
right lung	UBERON:0002167	94.88	gold quality
adrenal gland	UBERON:0002369	94.86	gold quality
lower esophagus mucosa	UBERON:0035834	94.83	gold quality
smooth muscle tissue	UBERON:0001135	94.80	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.79	gold quality
granulocyte	CL:0000094	94.77	gold quality
esophagus mucosa	UBERON:0002469	94.72	gold quality
pituitary gland	UBERON:0000007	94.70	gold quality
zone of skin	UBERON:0000014	94.69	gold quality
body of pancreas	UBERON:0001150	94.66	gold quality
omental fat pad	UBERON:0010414	94.66	gold quality
peritoneum	UBERON:0002358	94.64	gold quality
ascending aorta	UBERON:0001496	94.62	gold quality
thoracic aorta	UBERON:0001515	94.61	gold quality
coronary artery	UBERON:0001621	94.57	gold quality
upper lobe of lung	UBERON:0008948	94.54	gold quality
heart	UBERON:0000948	94.51	gold quality
right uterine tube	UBERON:0001302	94.51	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	94.48	gold quality
triceps brachii	UBERON:0001509	94.33	gold quality
sigmoid colon	UBERON:0001159	94.19	gold quality
Brodmann (1909) area 9	UBERON:0013540	94.16	gold quality
colon	UBERON:0001155	94.14	gold quality
mouth mucosa	UBERON:0003729	94.14	gold quality
descending thoracic aorta	UBERON:0002345	94.11	gold quality
nucleus accumbens	UBERON:0001882	94.05	gold quality
embryo	UBERON:0000922	93.97	gold quality
adipose tissue of abdominal region	UBERON:0007808	93.95	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	93.89	gold quality
large intestine	UBERON:0000059	93.79	gold quality
caudate nucleus	UBERON:0001873	93.72	gold quality
lymph node	UBERON:0000029	93.70	gold quality
stomach	UBERON:0000945	93.68	gold quality
thyroid gland	UBERON:0002046	93.68	gold quality
penis	UBERON:0000989	93.65	gold quality
cingulate cortex	UBERON:0003027	93.62	gold quality
intestine	UBERON:0000160	93.59	gold quality
frontal cortex	UBERON:0001870	93.59	gold quality
frontal lobe	UBERON:0016525	93.58	gold quality
spleen	UBERON:0002106	93.53	gold quality
small intestine	UBERON:0002108	93.53	gold quality
anterior cingulate cortex	UBERON:0009835	93.52	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-CURD-53	no	1694.27
E-MTAB-9689	no	265.83
E-GEOD-124858	no	17.71
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Skeletal muscle	tissue	160.3	low
Tongue	tissue	96.5
Frontal cortex	tissue	94.8
Caudate putamen	tissue	91.9
Cerebral cortex	tissue	87.3	high
Somatosensory cortex	tissue	87.3
Thalamus	tissue	83.5
Superior colliculi	tissue	82.6
Pons	tissue	81.5
Hippocampal formation	tissue	79.3
Midbrain	tissue	78.9
Occipital cortex	tissue	77.3
Medulla oblongata	tissue	75.6
Spinal cord	tissue	74.1
Postcentral gyrus	tissue	74.1
Locus coeruleus	tissue	73.0
Substantia nigra	tissue	72.0
Prefrontal cortex	tissue	71.5
Hypothalamus	tissue	70.3
Motor cortex	tissue	69.2
Temporal cortex	tissue	66.6
Retrosplenial and cingulate cortex	tissue	65.4
Entorhinal cortex	tissue	65.1
Cerebellum	tissue	64.9	high
Septum	tissue	64.0
Ventral forebrain	tissue	63.0
Putamen	tissue	62.8
Periaqueductal gray	tissue	61.8
Hippocampus	tissue	61.6	high
Liver	tissue	61.5	medium
Retrosplenial cortex	tissue	60.7
Corpus callosum	tissue	58.7
Basal ganglia	tissue	57.6	high
Nucleus accumbens	tissue	56.8
Choroid plexus	tissue	56.7
Insular cortex	tissue	56.7
Olfactory bulb	tissue	56.0
Thymus	tissue	53.0
Parathyroid gland	tissue	52.1	high
Amygdala	tissue	50.7
Vagina	tissue	50.6	medium
Heart muscle	tissue	50.5	high
Colon	tissue	49.7	medium
Skin 1	tissue	49.2	medium
Tonsil	tissue	47.9	high
Pituitary gland	tissue	46.3
Bone marrow	tissue	45.3	high
Appendix	tissue	44.9	medium
Adipose tissue	tissue	44.7	low
Placenta	tissue	44.5	high
Rectum	tissue	43.3	high
Lymph node	tissue	42.7	medium
Smooth muscle	tissue	42.2	low
Pancreas	tissue	41.4	high
Duodenum	tissue	40.8	medium
Ovary	tissue	40.1	medium
Salivary gland	tissue	39.6	low
Esophagus	tissue	39.2	high
Small intestine	tissue	39.1	high
Urinary bladder	tissue	38.9	medium

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Dorsal hippocampus (79.3), Ventral spinal cord (74.1), Ventral hippocampus (74.0), Pontine nuclei (71.4), Lateral hypothalamic area (70.3).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): BRCA2

miRNA regulators (miRDB)

Targeting PSMD3 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

23 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-5701	98.97	69.54	1502
HSA-MIR-4718	98.55	68.61	814
HSA-MIR-660-3P	98.14	66.04	1434
HSA-MIR-6801-3P	98.04	64.64	805
HSA-MIR-6810-3P	97.96	64.57	1023
HSA-MIR-556-5P	97.75	66.17	473
HSA-MIR-6747-3P	97.73	64.84	1596
HSA-MIR-3144-5P	97.64	65.45	646
HSA-MIR-10398-5P	97.12	64.94	1051

Functional genomics

gnomAD constraint: pLI 1, LOEUF 0.171, missense Z 2.59 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000264639 splits into 4 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
17:39,980,971–39,995,022	396 / 475.8	0.83	no
17:39,995,023–39,995,456	32 / 85.4	0.37	no
17:39,995,457–39,996,336	76 / 97.3	0.78	no
17:39,996,337–39,997,578	20 / 55.1	0.36	no
DepMap (CRISPR cell-line fitness): dependent in 100.0% of screened cell lines, common-essential.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): SU.86.86 (-3.592), HCC1143 (-3.577), KLE (-3.348), Panc 08.13 (-3.124), S-117 (-3.072), HSC-2 (-3.012), NIH:OVCAR-3 (-2.866), RERF-GC-1B (-2.84), C8166 (-2.815), AsPC-1 (-2.798), NCI-H1915 (-2.733), Daoy (-2.688), HPAF-II (-2.6), SK-LMS-1 (-2.59), RPMI-7951 (-2.559).

Literature-anchored findings (GeneRIF, showing 11)

• The significant contribution of PSMD3-CSF3 and PLCB4 loci to the regulation of neutrophil count, is demonstrated. (PMID:20172861)
• Study identified significantly white blood cell count (WBC) level associated SNPs of three separate genes GSDMA, MED24, and PSMD3 in European continent (EA) subjects. (PMID:22037903)
• HNF1A gene was associated with C-reactive protein, and the region including PSMD3 and CSF3 genes was associated with white blood cell count. (PMID:22788528)
• Our study suggests that PSMD3 variants are associated with insulin resistance in populations of different ancestries and that these relationships may also be modified by dietary factors. (PMID:23303871)
• A strong association between genetic variant rs2305482 in PSMD3 on chromosome 17 and IFN-induced neutropenia. (PMID:25515861)
• this study shows that haplotypes consisting of single nucleotide polymorphisms harboring PSMD3, CSF3 and MED24 genes are associated with asthma in Slovenian patients (PMID:27163155)
• In thyroid hemiagenesis, genomic examinations revealed the presence of four recurrent defects (three deletions and one duplication) affecting highly conservative proteasome genes PSMA1, PSMA3, and PSMD3. (PMID:28390009)
• Proteasome 26S subunit, non-ATPases 1 (PSMD1) and 3 (PSMD3), play an oncogenic role in chronic myeloid leukemia by stabilizing nuclear factor-kappa B. (PMID:33712704)
• 26S Proteasome Non-ATPase Regulatory Subunits 1 (PSMD1) and 3 (PSMD3) as Putative Targets for Cancer Prognosis and Therapy. (PMID:34572038)
• PSMD3 gene mutations cause pathological myopia. (PMID:36948574)
• PSMD3-ILF3 signaling cascade drives lung cancer cell proliferation and migration. (PMID:37337223)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	psmd3	ENSDARG00000018124
mus_musculus	Psmd3	ENSMUSG00000017221
rattus_norvegicus	Psmd3	ENSRNOG00000028103
caenorhabditis_elegans		WBGENE00004460

Paralogs (1): COPS3 (ENSG00000141030)

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
Bos taurus	Q2KJ46	97.4%	Diamond
Anopheles gambiae	O61470	94.0%	Diamond
Anopheles stephensi	Q9U5Z8	94.0%	Diamond
Arabidopsis thaliana	Q9LNU4	91.6%	Diamond
Nicotiana tabacum	P93768	87.5%	Diamond
Daucus carota	Q06364	87.5%	Diamond
Drosophila melanogaster	P25161	75.0%	Diamond
Dictyostelium discoideum	Q1ZXD3	48.3%	Diamond
Schizosaccharomyces pombe 972h-	O42897	45.2%	Diamond
Saccharomyces cerevisiae S288C	P40016	39.9%	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
GSDMA	protein-coding	284110
GSDMB	protein-coding	55876
ORMDL3	protein-coding	94103
LRRC3C	protein-coding	100505591
PSMD3-AS1	ncRNA	139432819
CSF3	protein-coding	1440
MIR6884	ncRNA	102466757
MED24	protein-coding	9862
SNORD124	snoRNA	101340251

Protein

Protein identifiers

26S proteasome non-ATPase regulatory subunit 3 — O43242 (reviewed: O43242)

Alternative names: 26S proteasome regulatory subunit RPN3, 26S proteasome regulatory subunit S3, Proteasome subunit p58

All UniProt accessions (3): O43242, F5H8K4, H0YGV8

UniProt curated annotations — full annotation on UniProt →

Function. Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.

Subunit / interactions. Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD3, a base containing 6 ATPases and few additional components. Interacts with UBQLN1 (via ubiquitin-like domain). Interacts with ERCC6.

Similarity. Belongs to the proteasome subunit S3 family.

Isoforms (2)

UniProt ID	Names	Canonical?
O43242-1	1	yes
O43242-2	2

RefSeq proteins (1): NP_002800* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000717	PCI_dom	Domain
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR013586	PSMD3_C	Domain
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR050756	CSN3	Family
IPR057985	TPR_PSMD3_N	Domain

Pfam: PF01399, PF08375, PF25573

Enzyme classification (BRENDA)

• EC 5.6.1.5 — proteasome ATPase (BRENDA: 37 organisms, 65 substrates, 19 inhibitors, 13 Km, 2 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.03–0.55	9
CTP	0.307–0.493	2
K48-GREEN-TAIL POLYPEPTIDE	0.0003	1
K48-RED POLYPEPTIDE	0.0044	1

UniProt features (64 total): helix 35, strand 9, turn 4, sequence conflict 3, compositionally biased region 3, cross-link 2, splice variant 2, region of interest 2, modified residue 2, chain 1, domain 1

Structure

Experimental structures (PDB)

showing 30 of 124 structures by resolution:

PDB	Title	Method	Resolution (Å)
9K53	Structure of substrate-engaged human 26S proteasome RP-CP subcomplex in state ED2.1	ELECTRON MICROSCOPY	2.5
8USB	Non-substrate-engaged human 26S proteasome with Nub1/FAT10 bound to Rpn1	ELECTRON MICROSCOPY	2.73
9MBP	Substrate-engaged human 26S proteasome bound to midnolin with RPT1 at top of spiral …	ELECTRON MICROSCOPY	2.75
9NKG	Structure of substrate engaged MIDN-bound human 26S proteasome, EB-MIDN (Composite map)	ELECTRON MICROSCOPY	2.8
9E8I	Human proteasome in resting state conformation bound to TXNL1 in Forward conformation	ELECTRON MICROSCOPY	2.87
9BV3	M1B Midnolin-Proteasome	ELECTRON MICROSCOPY	2.9
9E8H	Human proteasome in resting state conformation bound to TXNL1 in backward conformation	ELECTRON MICROSCOPY	2.9
9K4J	Structure of substrate-engaged human 26S proteasome RP-CP subcomplex in state EA1.0	ELECTRON MICROSCOPY	2.9
9NKF	Structure of human substrate-free 26S proteasome in the presence of ATPgS and …	ELECTRON MICROSCOPY	2.9
9U3L	Substrate-engaged human 26S proteasome bound to midnolin with RPT2 at top of spiral …	ELECTRON MICROSCOPY	2.91
9NKI	Structure of substrate engaged MIDN-bound human 26S proteasome, EB MIDN_UBL state …	ELECTRON MICROSCOPY	2.94
6MSB	Cryo-EM structures and dynamics of substrate-engaged human 26S proteasome	ELECTRON MICROSCOPY	3
7W37	Structure of USP14-bound human 26S proteasome in state EA1_UBL	ELECTRON MICROSCOPY	3
8CVT	Human 19S-20S proteasome, state SD2	ELECTRON MICROSCOPY	3
9E8G	Nub1/Fat10-processing human 26S proteasome bound to Txnl1 with Rpt5 at top of spiral …	ELECTRON MICROSCOPY	3.01
9PRT	Human 19S proteasome bound to TXNL1 PITH domain but with low density for RPT1, RPT2, and …	ELECTRON MICROSCOPY	3.02
9MBQ	Substrate-engaged human 26S proteasome bound to midnolin with RPT5 at top of spiral …	ELECTRON MICROSCOPY	3.08
7W38	Structure of USP14-bound human 26S proteasome in state EA2.0_UBL	ELECTRON MICROSCOPY	3.1
8USC	Nub1/Fat10-processing human 26S proteasome	ELECTRON MICROSCOPY	3.1
9BV1	M2A Midnolin-Proteasome (translocating)	ELECTRON MICROSCOPY	3.1
9E8O	Nub1/Fat10-processing human 26S proteasome bound to Txnl1 with Rpt2 at top of spiral …	ELECTRON MICROSCOPY	3.1
9K4R	Structure of substrate-engaged human 26S proteasome RP-CP subcomplex in state EB.1	ELECTRON MICROSCOPY	3.1
9E8Q	Nub1/Fat10-processing human 26S proteasome with Rpt2 at top of spiral staircase	ELECTRON MICROSCOPY	3.16
6MSD	Cryo-EM structures and dynamics of substrate-engaged human 26S proteasome	ELECTRON MICROSCOPY	3.2
6MSK	Cryo-EM structures and dynamics of substrate-engaged human 26S proteasome	ELECTRON MICROSCOPY	3.2
7W39	Structure of USP14-bound human 26S proteasome in state EA2.1_UBL	ELECTRON MICROSCOPY	3.2
7W3G	Structure of USP14-bound human 26S proteasome in substrate-engaged state ED2.0_USP14	ELECTRON MICROSCOPY	3.2
7W3H	Structure of USP14-bound human 26S proteasome in substrate-engaged state ED2.1_USP14	ELECTRON MICROSCOPY	3.2
9K4M	Structure of substrate-engaged human 26S proteasome RP-CP subcomplex in state EA2.1	ELECTRON MICROSCOPY	3.2
9K4Y	Structure of substrate-engaged human 26S proteasome RP-CP subcomplex in state ED0.3	ELECTRON MICROSCOPY	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43242-F1	73.25	0.05

Human Protein Atlas

Protein class: Predicted intracellular proteins, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm; cytosol

Antibody reliability (HPA): IH approved · IF enhanced

Functional residue map

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

Post-translational modifications (4)

Type	Positions
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in sumo2)	38
Phosphoserine	418, 430
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in sumo1)	38

Function

Pathways and Gene Ontology

Reactome pathways

58 curated (TAS) of 172; 13 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

showing 60 of 172 pathways:

ID	Pathway	Evidence
R-HSA-5678895	Defective CFTR causes cystic fibrosis ⚕	curated
R-HSA-5362768	Hh mutants are degraded by ERAD ⚕	curated
R-HSA-180585	Vif-mediated degradation of APOBEC3G ⚕	curated
R-HSA-180534	Vpu mediated degradation of CD4 ⚕	curated
R-HSA-382556	ABC-family protein mediated transport	curated
R-HSA-9931269	AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)	curated
R-HSA-174154	APC/C:Cdc20 mediated degradation of Securin	curated
R-HSA-174178	APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1	curated
R-HSA-450408	AUF1 (hnRNP D0) binds and destabilizes mRNA	curated
R-HSA-1169091	Activation of NF-kappaB in B cells	curated
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation	curated
R-HSA-68867	Assembly of the pre-replicative complex	curated
R-HSA-4608870	Asymmetric localization of PCP proteins	curated
R-HSA-174084	Autodegradation of Cdh1 by Cdh1:APC/C	curated
R-HSA-349425	Autodegradation of the E3 ubiquitin ligase COP1	curated
R-HSA-69017	CDK-mediated phosphorylation and removal of Cdc6	curated
R-HSA-5607764	CLEC7A (Dectin-1) signaling	curated
R-HSA-174184	Cdc20:Phospho-APC/C mediated degradation of Cyclin A	curated
R-HSA-1236978	Cross-presentation of soluble exogenous antigens (endosomes)	curated
R-HSA-5607761	Dectin-1 mediated noncanonical NF-kB signaling	curated
R-HSA-4641257	Degradation of AXIN	curated
R-HSA-9766229	Degradation of CDH1	curated
R-HSA-4641258	Degradation of DVL	curated
R-HSA-5610780	Degradation of GLI1 by the proteasome	curated
R-HSA-195253	Degradation of beta-catenin by the destruction complex	curated
R-HSA-202424	Downstream TCR signaling	curated
R-HSA-8854050	FBXL7 down-regulates AURKA during mitotic entry and in early mitosis	curated
R-HSA-2871837	FCERI mediated NF-kB activation	curated
R-HSA-69481	G2/M Checkpoints	curated
R-HSA-5610785	GLI3 is processed to GLI3R by the proteasome	curated
R-HSA-9762114	GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2	curated
R-HSA-9929356	GSK3B-mediated proteasomal degradation of PD-L1(CD274)	curated
R-HSA-5632684	Hedgehog ‘on’ state	curated
R-HSA-5358346	Hedgehog ligand biogenesis	curated
R-HSA-9020702	Interleukin-1 signaling	curated
R-HSA-9755511	KEAP1-NFE2L2 pathway	curated
R-HSA-5687128	MAPK6/MAPK4 signaling	curated
R-HSA-5676590	NIK–>noncanonical NF-kB signaling	curated
R-HSA-8951664	Neddylation	curated
R-HSA-9974237	Negative Regulation of DNA Double Strand Break Response	curated
R-HSA-6798695	Neutrophil degranulation	curated
R-HSA-68949	Orc1 removal from chromatin	curated
R-HSA-1234176	Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha	curated
R-HSA-8939236	RUNX1 regulates transcription of genes involved in differentiation of HSCs	curated
R-HSA-8948751	Regulation of PTEN stability and activity	curated
R-HSA-5658442	Regulation of RAS by GAPs	curated
R-HSA-8941858	Regulation of RUNX3 expression and activity	curated
R-HSA-350562	Regulation of ornithine decarboxylase (ODC)	curated
R-HSA-187577	SCF(Skp2)-mediated degradation of p27/p21	curated
R-HSA-174113	SCF-beta-TrCP mediated degradation of Emi1	curated
R-HSA-9929491	SPOP-mediated proteasomal degradation of PD-L1(CD274)	curated
R-HSA-2467813	Separation of Sister Chromatids	curated
R-HSA-5668541	TNFR2 non-canonical NF-kB pathway	curated
R-HSA-8852276	The role of GTSE1 in G2/M progression after G2 checkpoint	curated
R-HSA-5689603	UCH proteinases	curated
R-HSA-5689880	Ub-specific processing proteases	curated
R-HSA-69601	Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A	curated
R-HSA-75815	Ubiquitin-dependent degradation of Cyclin D	curated
R-HSA-5619084	ABC transporter disorders ⚕	—
R-HSA-1643685	Disease ⚕	—

MSigDB gene sets: 342 (showing top): REACTOME_DNA_REPLICATION, REACTOME_SIGNALING_BY_NOTCH, SHEPARD_BMYB_MORPHOLINO_UP, REACTOME_APC_C_CDH1_MEDIATED_DEGRADATION_OF_CDC20_AND_OTHER_APC_C_CDH1_TARGETED_PROTEINS_IN_LATE_MITOSIS_EARLY_G1, REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, WHITEHURST_PACLITAXEL_SENSITIVITY, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, KEGG_PROTEASOME, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOCC_SECRETORY_GRANULE, GCANCTGNY_MYOD_Q6, REACTOME_SCF_SKP2_MEDIATED_DEGRADATION_OF_P27_P21

GO Biological Process (7): ubiquitin-dependent protein catabolic process (GO:0006511), response to oxidative stress (GO:0006979), proteasomal protein catabolic process (GO:0010498), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), regulation of proteasomal protein catabolic process (GO:0061136), cellular response to type I interferon (GO:0071357), regulation of protein catabolic process (GO:0042176)

GO Molecular Function (2): enzyme regulator activity (GO:0030234), protein binding (GO:0005515)

GO Cellular Component (13): proteasome complex (GO:0000502), extracellular region (GO:0005576), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), synaptic vesicle (GO:0008021), proteasome regulatory particle, lid subcomplex (GO:0008541), membrane (GO:0016020), proteasome accessory complex (GO:0022624), secretory granule lumen (GO:0034774), extracellular exosome (GO:0070062), ficolin-1-rich granule lumen (GO:1904813), proteasome regulatory particle (GO:0005838)

Reactome top-level categories

18 top-level categories:

Category	Pathways
Antigen processing-Cross presentation	2
APC/C-mediated degradation of cell cycle proteins	2
Host Interactions of HIV factors	2
Downstream signaling events of B Cell Receptor (BCR)	1
Cellular response to hypoxia	1
Regulation of APC/C activators between G1/S and early anaphase	1
APC/C:Cdc20 mediated degradation of mitotic proteins	1
APC:Cdc20 mediated degradation of cell cycle proteins prior to satisfation of the cell cycle checkpoint	1
Cyclin E associated events during G1/S transition	1
Cyclin A:Cdk2-associated events at S phase entry	1
Signaling by WNT	1
TCR signaling	1
Regulation of Apoptosis	1
Mitotic Anaphase	1
Fc epsilon receptor (FCERI) signaling	1
Stabilization of p53	1
Metabolism of polyamines	1
Transport of small molecules	1

GO top-level categories

32 GO namespaces:

Category	Terms
cellular anatomical structure	4
protein-containing complex	3
protein catabolic process	2
proteasomal protein catabolic process	2
protein ubiquitination	1
modification-dependent protein catabolic process	1
response to stress	1
ubiquitin-dependent protein catabolic process	1
regulation of protein catabolic process	1
response to type I interferon	1
cellular response to cytokine stimulus	1
regulation of catabolic process	1
regulation of protein metabolic process	1
catalytic activity	1
molecular function regulator activity	1
binding	1
intracellular protein-containing complex	1
endopeptidase complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1
exocytic vesicle	1
presynapse	1
proteasome regulatory particle	1
proteasome complex	1
intracellular anatomical structure	1
secretory granule	1
cytoplasmic vesicle lumen	1
extracellular vesicle	1
intracellular organelle lumen	1
ficolin-1-rich granule	1
proteasome accessory complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 6 of 22 annotations. The rest are phylogenetic / computational / electronic (IEA).

6 experimentally-supported GO terms:

GO term	NS	Evidence
cytosol	CC	direct assay
extracellular exosome	CC	high-throughput assay
membrane	CC	high-throughput assay
nucleoplasm	CC	direct assay
nucleus	CC	high-throughput assay
proteasome complex	CC	direct assay

Protein interactions and networks

STRING

showing 15 of 2,326 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PSMD3	PSMD12	O00232	865
PSMD3	PSMD8	P48556	854
PSMD3	PSMD6	Q15008	850
PSMD3	PSMD13	Q9UNM6	847
PSMD3	PSMD11	O00231	841
PSMD3	PSMD14	O00487	841
PSMD3	PSMD7	P51665	837
PSMD3	PSMD4	P55036	836
PSMD3	PSMC4	P43686	802
PSMD3	ADRM1	Q16186	793
PSMD3	PSMD1	Q99460	771
PSMD3	PSMD2	Q13200	751
PSMD3	PSMC2	P35998	703
PSMD3	PSMC1	P49014	699
PSMD3	PSMC5	P47210	668

IntAct

Human interaction partners of PSMD3 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 37 partners by confidence:

Partner	Interaction type	MIscore	Records
ZBTB43	physical association	0.780	7
PSMD2	physical association	0.740	1
PSMC5	association	0.730	2
PSMA6	physical association	0.670	3
SEM1	physical association	0.670	3
PSMD6	association	0.670	2
PSMD4	physical association	0.670	1
PSMD11	association	0.650	1
CEP44	physical association	0.560	3
HTT	physical association	0.560	3
NFKBIA	physical association	0.560	3
PRPF3	physical association	0.560	3
PSMC4	association	0.530	1
PLCG2	physical association	0.510	2
PTP4A1	association	0.420	2
AARSD1	physical association	0.400	1
FKBPL	physical association	0.400	1
MLF1	physical association	0.400	1
MLF2	physical association	0.400	1
PLEC	physical association	0.400	1
DUSP15	association	0.350	1
MYLK2	association	0.350	1
PSMD1	association	0.350	1
ACTR3B	physical association	0.000	1
BRF2	physical association	0.000	1
FTSJ1	physical association	0.000	1
GH1	physical association	0.000	1
HLA-B	physical association	0.000	1
IKBKE	physical association	0.000	1
NFKB2	physical association	0.000	1

BioGRID (1,221 interactions; top human partners by supporting records in a sample of 600 records): PSMD8 (Co-fractionation; 13 records), PSMD6 (Co-fractionation; 12 records), PSMD7 (Affinity Capture-MS; 10 records), PSMC4 (Co-fractionation; 9 records), PSMC5 (Co-fractionation; 9 records), PSMD14 (Co-fractionation; 8 records), PSMD1 (Co-fractionation; 7 records), ADRM1 (Affinity Capture-MS; 6 records), PSMA2 (Co-fractionation; 6 records), PSMD10 (Co-fractionation; 6 records), PSMD12 (Co-fractionation; 6 records), PSMD13 (Co-fractionation; 6 records), PSMD2 (Co-fractionation; 6 records), PSMD4 (Co-fractionation; 6 records), PAAF1 (Affinity Capture-MS; 5 records)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
PSMD3	“form complex”	“26S Proteasome”	binding

Protein complexes (CORUM) (2)

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

2 complexes by size:

Complex	Subunits	Members
★ PA700-20S-PA28 complex	36	PSMA5, PSMD4, PSMD6, PSMD9, PSME1, PSME2, PSMD11, PSMB1, PSMB4, PSMC1, PSMA3, PSMB5, PSMD10, PSMA7, PSMC5, PSMD14, PSMD7, PSMA6, PSMB6, PSMD12, PSMD3, PSMD1, PSMA4, PSMB7, PSMC3, PSMC4, PSMC6, PSMD8, PSMB3, PSMC2, PSMD13, PSMA1, PSMA2, PSMB2, PSMD2, PSMD5
PA700 complex	20	PSMD6, PSMD7, PSMC2, PSMC3, PSMD12, PSMD14, PSMD9, PSMD10, PSMD11, PSMD2, PSMD4, PSMC4, PSMC5, PSMD8, PSMC1, PSMC6, PSMD1, PSMD13, PSMD3, PSMD5

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 37 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
Regulation of activated PAK-2p34 by proteasome mediated degradation	9	96.4×	4e-15
Proteasome assembly	12	94.1×	1e-19
Regulation of ornithine decarboxylase (ODC)	9	94.1×	4e-15
Vpu mediated degradation of CD4	9	91.9×	4e-15
Autodegradation of the E3 ubiquitin ligase COP1	9	91.9×	4e-15
Ubiquitin-dependent degradation of Cyclin D	9	91.9×	4e-15
NIK–>noncanonical NF-kB signaling	10	87.8×	3e-16
Cross-presentation of soluble exogenous antigens (endosomes)	9	87.8×	5e-15

GO biological processes:

GO term	Partners	Fold	FDR
proteasome-mediated ubiquitin-dependent protein catabolic process	10	14.9×	2e-07

Disease & clinical

Genetic variants

Variant evidence for PSMD3: 74 ClinVar records (1 pathogenic / likely pathogenic); 30 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	48
Likely benign	4
Benign	1

Top pathogenic / likely-pathogenic (1)

Showing all 1 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
369988	GRCh37/hg19 17q21.1(chr17:38146929-38153473)x1	Likely pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore PSMD3’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; 41 predictions of 828):

Position(s)	Effect	Δscore	Sites
17:39984292–39984293	acceptor_loss	1.0000	6
17:39984485–39984486	donor_loss	1.0000	4
17:39986573–39986574	acceptor_loss	1.0000	6
17:39988681–39988682	acceptor_loss	1.0000	6
17:39988820–39988821	donor_loss	1.0000	6
17:39989734	acceptor_gain	1.0000
17:39989737	acceptor_gain	1.0000
17:39989737–39989738	acceptor_loss	1.0000	5
17:39989930–39989931	donor_loss	1.0000	5
17:39990087	acceptor_gain	1.0000

AlphaMissense

1,927 missense substitutions predicted likely pathogenic (of 3,479 scored), across 423 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
M494	9	0.935	0.999
M525	9	0.910	0.998
M37	9	0.834	0.965
F324	8	0.996	1.000
D444	8	0.996	0.999
F348	8	0.989	1.000
F375	8	0.985	1.000
D433	8	0.984	0.997
D518	8	0.982	0.998
D204	8	0.974	0.991
F386	8	0.965	0.999
F482	8	0.946	0.999
D465	8	0.944	0.990
D243	8	0.940	0.981
H487	8	0.935	0.999
H400	8	0.934	0.993
D389	8	0.921	0.991
D504	8	0.888	0.982
N252	8	0.884	0.998
D74	8	0.875	0.981

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

1 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (validation)	unfavorable	4.19e-06

Disease associations

OMIM: gene MIM:617676 | disease phenotypes:

GWAS associations

30 associations:

Study	Trait	p-value
GCST90002389_98	Lymphocyte percentage of white cells	2e-118
GCST004632_17	Lymphocyte percentage of white cells	2e-108
GCST90002394_392	Monocyte percentage of white cells	3e-82
GCST008916_121	Asthma	2e-62
GCST005973_8	White blood cell count	9e-62
GCST004618_20	White blood cell count (basophil)	2e-47
GCST001137_10	White blood cell count	9e-35
GCST001137_8	White blood cell count	2e-31
GCST002557_3	Neutrophil count	9e-25
GCST002556_12	White blood cell count	3e-23
GCST002557_7	Neutrophil count	4e-23
GCST005038_26	Allergic disease (asthma, hay fever or eczema)	8e-22
GCST002556_6	White blood cell count	3e-19
GCST001134_16	White blood cell types	4e-16
GCST004624_12	Sum eosinophil basophil counts	2e-14
GCST000589_2	White blood cell count	3e-14
GCST008916_86	Asthma	6e-13
GCST001302_4	White blood cell count	1e-12
GCST001302_2	White blood cell count	2e-12
GCST008916_5	Asthma	2e-12
GCST002556_13	White blood cell count	3e-12
GCST004128_2	White blood cell count (neutrophil)	5e-11
GCST002557_8	Neutrophil count	7e-11
GCST005056_1	Neutrophil count	2e-10
GCST000600_2	Neutrophil count	6e-10
GCST006014_25	Creatine kinase levels	3e-9
GCST012232_28	Lipoprotein (a) levels	1e-8
GCST007399_2	Mitochondrial DNA copy number	2e-7
GCST008103_47	Bipolar disorder	6e-7
GCST007395_3	Mitochondrial DNA copy number	7e-7

EFO canonical traits (from GWAS)

8 canonical traits:

EFO ID	Trait name
EFO:0004833	neutrophil count
EFO:0005090	basophil count
EFO:0004842	eosinophil count
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0004534	creatine kinase measurement
EFO:0006312	mitochondrial DNA measurement
EFO:0006925	lipoprotein A measurement
EFO:0007989	monocyte percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2364701 (PROTEIN COMPLEX), CHEMBL3831210 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 26,571 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

2 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL325041	BORTEZOMIB	4	13,415
CHEMBL451887	CARFILZOMIB	4	13,156

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

1 measured of 1 human assays (2 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5653589	KD	1440 nM

ChEMBL bioactivities

66 potent at pChembl≥5 of 67 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.62	IC50	2.4	nM	BORTEZOMIB
8.59	IC50	2.56	nM	BORTEZOMIB
8.57	IC50	2.7	nM	CHEMBL3237863
8.47	IC50	3.4	nM	CHEMBL6143686
8.41	IC50	3.9	nM	CHEMBL3237862
8.39	IC50	4.1	nM	CHEMBL3237864
8.39	IC50	4.1	nM	CHEMBL3237867
8.32	IC50	4.8	nM	CHEMBL3237873
8.29	IC50	5.1	nM	CHEMBL3237865
8.24	IC50	5.7	nM	CHEMBL3237866
8.24	IC50	5.7	nM	CHEMBL3237860
8.23	IC50	5.9	nM	CHEMBL3237868
8.15	IC50	7	nM	BORTEZOMIB
8.15	IC50	7.1	nM	CHEMBL3237870
8.15	IC50	7.14	nM	BORTEZOMIB
8.12	IC50	7.5	nM	CHEMBL3237871
8.11	IC50	7.7	nM	CHEMBL3237874
8.11	IC50	7.8	nM	CHEMBL3237869
8.07	IC50	8.6	nM	CARFILZOMIB
7.71	Kd	19.67	nM	CHEMBL5653589
7.71	ED50	19.67	nM	CHEMBL5653589
7.54	IC50	29	nM	CHEMBL3237861
7.34	IC50	46	nM	CHEMBL3237867
7.27	IC50	54	nM	CHEMBL3237872
7.12	IC50	75	nM	CHEMBL3237865
7.12	IC50	76	nM	CHEMBL3237866
6.96	IC50	110	nM	CHEMBL3262766
6.92	IC50	120	nM	CHEMBL3237864
6.92	IC50	120	nM	BORTEZOMIB
6.89	IC50	130	nM	CHEMBL3237869
6.85	IC50	140	nM	CHEMBL3237862
6.82	IC50	150	nM	CHEMBL3237863
6.77	IC50	170	nM	CHEMBL3237873
6.77	IC50	170	nM	CHEMBL3262765
6.72	IC50	190	nM	CHEMBL3262758
6.68	IC50	210	nM	CHEMBL3237870
6.66	IC50	220	nM	CHEMBL3262756
6.60	IC50	250	nM	CHEMBL3237868
6.47	IC50	340	nM	CHEMBL3262752
6.47	IC50	340	nM	CHEMBL3262755
6.44	IC50	360	nM	CHEMBL3262757
6.42	IC50	380	nM	CHEMBL3262754
6.36	IC50	440	nM	CHEMBL3262753
6.30	IC50	500	nM	CHEMBL3237872
6.20	IC50	630	nM	CHEMBL3262762
6.02	IC50	950	nM	CHEMBL3262761
6.00	IC50	1000	nM	CHEMBL3237871
5.96	IC50	1100	nM	CHEMBL3237862
5.85	IC50	1400	nM	BELACTOSIN A
5.84	IC50	1440	nM	BELACTOSIN A

PubChem BioAssay actives

63 with measured affinity, of 139 total; 35 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
Bortezomib	1985684: Inhibition of 26S proteasome (unknown origin)	ic50	0.0024	uM
(2S)-2-acetamido-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-[4-phenylmethoxy-3-(phenylmethoxymethyl)butyl]butanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0027	uM
4-methyl-N-[(2R)-1-[[(2R)-4-methyl-1-[(2S)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]-4-phenylbutanoyl]amino]pentanamide	2236585: Activation of 26s proteosome (unknown origin)	ic50	0.0034	uM
(2S)-2-acetamido-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-[3-phenylmethoxy-2-(phenylmethoxymethyl)propyl]butanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0039	uM
(2S)-2-acetamido-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-[5-phenylmethoxy-4-(phenylmethoxymethyl)pentyl]butanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0041	uM
(2S)-2-acetamido-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-[5-phenylmethoxy-4-(phenylmethoxymethyl)pentyl]pentanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0041	uM
(2S)-2-acetamido-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-(4-phenylmethoxybutyl)butanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0048	uM
(2S)-2-acetamido-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-[3-phenylmethoxy-2-(phenylmethoxymethyl)propyl]pentanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0051	uM
(2S)-2-acetamido-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-[4-phenylmethoxy-3-(phenylmethoxymethyl)butyl]pentanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0057	uM
benzyl N-[(2S)-1-[[(2R)-1-[(1R,2S)-2-[[(2R,3S)-3-[(2S)-butan-2-yl]-4-oxooxetane-2-carbonyl]amino]cyclopropyl]-4-phenylbutan-2-yl]amino]-1-oxopropan-2-yl]carbamate	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0057	uM
(2S)-2-[(2,5-dichlorobenzoyl)amino]-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-[4-phenylmethoxy-3-(phenylmethoxymethyl)butyl]butanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0059	uM
(2S)-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-[4-phenylmethoxy-3-(phenylmethoxymethyl)butyl]-2-(pyrazine-2-carbonylamino)butanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0071	uM
(2S)-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-[4-phenylmethoxy-3-(phenylmethoxymethyl)butyl]-2-[(6-phenylpyridine-2-carbonyl)amino]butanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0075	uM
[(1R)-1-[[(2S)-2-acetamido-4-oxo-4-[[3-phenylmethoxy-2-(phenylmethoxymethyl)propyl]amino]butanoyl]amino]-3-methylbutyl]boronic acid	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0077	uM
(2S)-2-benzamido-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-[4-phenylmethoxy-3-(phenylmethoxymethyl)butyl]butanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0078	uM
Carfilzomib	1141825: Inhibition of chymotrypsin-like enzyme activity of purified human 20S proteasome using Suc-Leu-Leu-Val-Tyr-AMC as substrate by fluorescence method	ic50	0.0086	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149127: Binding affinity to human PSMD3 incubated for 45 mins by Kinobead based pull down assay	kd	0.0197	uM
(2R,3S)-3-[(2S)-butan-2-yl]-4-oxo-N-[4-phenylmethoxy-3-(phenylmethoxymethyl)butyl]oxetane-2-carboxamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0290	uM
(2S)-2-acetamido-N’-methyl-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]butanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0540	uM
N-[(1R)-3-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-oxo-1-phenylpropyl]naphthalene-2-carboxamide	1141825: Inhibition of chymotrypsin-like enzyme activity of purified human 20S proteasome using Suc-Leu-Leu-Val-Tyr-AMC as substrate by fluorescence method	ic50	0.1100	uM
N-[(1R)-3-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-oxo-1-phenylpropyl]-4-(trifluoromethyl)benzamide	1141825: Inhibition of chymotrypsin-like enzyme activity of purified human 20S proteasome using Suc-Leu-Leu-Val-Tyr-AMC as substrate by fluorescence method	ic50	0.1700	uM
N-[3-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-oxo-1-phenylpropyl]naphthalene-2-carboxamide	1141825: Inhibition of chymotrypsin-like enzyme activity of purified human 20S proteasome using Suc-Leu-Leu-Val-Tyr-AMC as substrate by fluorescence method	ic50	0.1900	uM
N-[3-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-oxo-1-phenylpropyl]-4-(trifluoromethyl)benzamide	1141825: Inhibition of chymotrypsin-like enzyme activity of purified human 20S proteasome using Suc-Leu-Leu-Val-Tyr-AMC as substrate by fluorescence method	ic50	0.2200	uM
N-[3-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-oxo-1-phenylpropyl]pyridine-3-carboxamide	1141825: Inhibition of chymotrypsin-like enzyme activity of purified human 20S proteasome using Suc-Leu-Leu-Val-Tyr-AMC as substrate by fluorescence method	ic50	0.3400	uM
4-methoxy-N-[3-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-oxo-1-phenylpropyl]benzamide	1141825: Inhibition of chymotrypsin-like enzyme activity of purified human 20S proteasome using Suc-Leu-Leu-Val-Tyr-AMC as substrate by fluorescence method	ic50	0.3400	uM
4-cyano-N-[3-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-oxo-1-phenylpropyl]benzamide	1141825: Inhibition of chymotrypsin-like enzyme activity of purified human 20S proteasome using Suc-Leu-Leu-Val-Tyr-AMC as substrate by fluorescence method	ic50	0.3600	uM
4-fluoro-N-[3-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-oxo-1-phenylpropyl]benzamide	1141825: Inhibition of chymotrypsin-like enzyme activity of purified human 20S proteasome using Suc-Leu-Leu-Val-Tyr-AMC as substrate by fluorescence method	ic50	0.3800	uM
N-[3-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-oxo-1-phenylpropyl]benzamide	1141825: Inhibition of chymotrypsin-like enzyme activity of purified human 20S proteasome using Suc-Leu-Leu-Val-Tyr-AMC as substrate by fluorescence method	ic50	0.4400	uM
N-[3-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-oxo-1-phenylpropyl]oxane-4-carboxamide	1141825: Inhibition of chymotrypsin-like enzyme activity of purified human 20S proteasome using Suc-Leu-Leu-Val-Tyr-AMC as substrate by fluorescence method	ic50	0.6300	uM
N-[3-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-oxo-1-phenylpropyl]thiophene-2-carboxamide	1141825: Inhibition of chymotrypsin-like enzyme activity of purified human 20S proteasome using Suc-Leu-Leu-Val-Tyr-AMC as substrate by fluorescence method	ic50	0.9500	uM
(2S)-2-[[(2S)-2-aminopropanoyl]amino]-3-[(1S,2S)-2-[[(2R,3S)-3-[(2S)-butan-2-yl]-4-oxooxetane-2-carbonyl]amino]cyclopropyl]propanoic acid	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	1.4000	uM
(2S)-2-acetamido-N-[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]-N’-[4-phenylmethoxy-3-(phenylmethoxymethyl)butyl]butanediamide	1152964: Inhibition of chymotrypsin-like of human 20S proteasome using chromophoric Suc-LLVY-AMC as substrate after 60 mins by fluorescence assay	ic50	2.3000	uM
N-[3-(2-oxo-1,3,4-oxathiazol-5-yl)phenyl]acetamide	1137840: Inhibition of chymotrypsin-like activity of 26S proteasome in intact human Karpas 1106p cells assessed as substrate hydrolysis using Suc-LLVY-(D)-aminoluciferin as substrate after 3 hrs by cell-based Proteasome-Glo assay	ec50	4.2000	uM
(2S)-2-acetamido-N-[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]-N’-(4-phenylmethoxybutyl)butanediamide	1152964: Inhibition of chymotrypsin-like of human 20S proteasome using chromophoric Suc-LLVY-AMC as substrate after 60 mins by fluorescence assay	ic50	5.7000	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149127: Binding affinity to human PSMD3 incubated for 45 mins by Kinobead based pull down assay	kd	6.2161	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression, affects cotreatment, decreases expression	4
sodium arsenite	decreases expression, increases expression	3
Cyclosporine	increases expression	3
Arsenic Trioxide	decreases reaction, increases expression, affects binding	2
Smoke	decreases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
bisphenol A	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression	1
kojic acid	decreases expression	1
cobaltous chloride	increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	decreases methylation	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	increases expression	1
CGP 52608	affects binding, increases reaction	1
CD 437	decreases expression	1
3-(4’-hydroxy-3’-adamantylbiphenyl-4-yl)acrylic acid	decreases expression	1
bisphenol B	increases expression	1
abrine	increases expression	1
bisphenol AF	increases expression	1
Arbutin	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Diazinon	increases methylation	1
Environmental Pollutants	affects expression	1
Furaldehyde	affects cotreatment, affects localization, increases expression	1
Hydralazine	decreases expression, affects cotreatment	1
Ivermectin	decreases expression	1

ChEMBL screening assays

27 unique, capped per target: 27 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3222879	Binding	Inhibition of human 20S proteasome using Suc-LLVY-AMC as substrate preincubated for 30 mins followed by substrate addition measured after 90 mins by fluorescence assay	Oxathiazole-2-one derivative of bortezomib: Synthesis, stability and proteasome inhibition activity — *Medchemcomm*

Clinical trials (associated diseases)

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

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for PSMD3 across ~30M SureChEMBL compounds — explore on Sugi Predict.