PSMA6

Summary

PSMA6 (proteasome 20S subunit alpha 6, HGNC:9535) is a protein-coding gene on chromosome 14q13.2, encoding Proteasome subunit alpha type-6 (P60900). Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. It is a common-essential gene (DepMap: required in 100.0% of cancer cell lines).

The proteasome is a multicatalytic proteinase complex with a highly ordered ring-shaped 20S core structure. The core structure 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. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. This gene encodes a member of the peptidase T1A family, that is a 20S core alpha subunit. Multiple transcript variants encoding several different isoforms have been found for this gene. A pseudogene has been identified on the Y chromosome.

Source: NCBI Gene 5687 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 3 total — 1 pathogenic
• Druggable target: yes — 6 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 100.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_002791

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9535
Approved symbol	PSMA6
Name	proteasome 20S subunit alpha 6
Location	14q13.2
Locus type	gene with protein product
Status	Approved
Aliases	IOTA, PROS27, p27K, MGC22756, MGC2333, MGC23846
Ensembl gene	ENSG00000100902
Ensembl biotype	protein_coding
OMIM	602855
Entrez	5687

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 18 protein_coding, 4 nonsense_mediated_decay, 4 retained_intron

ENST00000261479, ENST00000540871, ENST00000553688, ENST00000553809, ENST00000554457, ENST00000554541, ENST00000554620, ENST00000554843, ENST00000554961, ENST00000555050, ENST00000555764, ENST00000556167, ENST00000556221, ENST00000556506, ENST00000622405, ENST00000627895, ENST00000628955, ENST00000884202, ENST00000884203, ENST00000884204, ENST00000884205, ENST00000929332, ENST00000929333, ENST00000929334, ENST00000929335, ENST00000949003

RefSeq mRNA: 4 — MANE Select: NM_002791 NM_001282232, NM_001282233, NM_001282234, NM_002791

CCDS: CCDS61437, CCDS61438, CCDS9655

Canonical transcript exons

ENST00000261479 — 7 exons

Exon	Start	End
ENSE00001177230	35292382	35292552
ENSE00002514756	35317249	35317493
ENSE00003495083	35314361	35314455
ENSE00003514915	35312881	35313059
ENSE00003538402	35307994	35308088
ENSE00003555628	35308914	35308995
ENSE00003638739	35310740	35310895

Expression profiles

Bgee: expression breadth ubiquitous, 137 present calls, max score 99.39.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 120.5072 / max 1086.0913, expressed in 1827 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
139226	109.1864	1826
139225	8.3664	1711
139224	2.7588	1338
139222	0.0832	26
139219	0.0523	3
139218	0.0377	4
139220	0.0182	4
139223	0.0042	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	99.39	gold quality
right testis	UBERON:0004534	99.39	gold quality
islet of Langerhans	UBERON:0000006	99.01	gold quality
testis	UBERON:0000473	98.88	gold quality
monocyte	CL:0000576	98.82	gold quality
gastrocnemius	UBERON:0001388	98.78	gold quality
leukocyte	CL:0000738	98.77	gold quality
muscle of leg	UBERON:0001383	98.75	gold quality
calcaneal tendon	UBERON:0003701	98.69	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.55	gold quality
placenta	UBERON:0001987	98.54	gold quality
endometrium	UBERON:0001295	98.46	gold quality
rectum	UBERON:0001052	98.45	gold quality
cortical plate	UBERON:0005343	98.44	gold quality
vermiform appendix	UBERON:0001154	98.43	gold quality
mucosa of transverse colon	UBERON:0004991	98.40	gold quality
right adrenal gland	UBERON:0001233	98.38	gold quality
right adrenal gland cortex	UBERON:0035827	98.35	gold quality
lymph node	UBERON:0000029	98.34	gold quality
left adrenal gland	UBERON:0001234	98.28	gold quality
adrenal tissue	UBERON:0018303	98.27	gold quality
right lung	UBERON:0002167	98.25	gold quality
bone marrow	UBERON:0002371	98.24	gold quality
adrenal gland	UBERON:0002369	98.23	gold quality
left adrenal gland cortex	UBERON:0035825	98.23	gold quality
ganglionic eminence	UBERON:0004023	98.18	gold quality
smooth muscle tissue	UBERON:0001135	98.17	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.15	gold quality
upper lobe of left lung	UBERON:0008952	98.15	gold quality
muscle tissue	UBERON:0002385	98.13	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	62.30
E-CURD-112	yes	20.36
E-ANND-3	yes	15.41
E-MTAB-10042	yes	12.01

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): JUN, NFKB

miRNA regulators (miRDB)

13 targeting PSMA6, 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-4481	100.00	66.42	1669
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-6861-3P	99.60	68.46	444
HSA-MIR-4312	99.34	67.30	511
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-8085	99.28	67.56	2362
HSA-MIR-4490	98.51	68.47	943
HSA-MIR-5087	98.01	69.09	965
HSA-MIR-5007-5P	97.95	64.71	614
HSA-MIR-7113-5P	97.88	67.33	1735
HSA-MIR-4781-3P	95.78	65.66	572

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 100.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 24)

• common SNP (minor allele frequency of 0.35) in the proteasome subunit alpha type 6 gene (PSMA6) conferring risk of myocardial infarction in the Japanese population (PMID:16845397)
• The reported genotype in PSMA6 appears not to contribute appreciably to myocardial infarction, but may contribute slightly to atherosclerosis in the present study population. (PMID:17384448)
• 2 SNPs at positions -110 & -8 from translation start, in the promoter region & 5’UTR of PSMA6 were analyzed; genotype -8CG was more frequent in type 2 diabetes patients & haplotype C-110/G-8, compared to C-110/C-8 was associated with higher risk of NIDDM (PMID:17555133)
• The GG genotype for rs1048990 was less frequent in the UK population than in the Japanese population, and was associated with an odds ratio for mi of 1.09 per G allele in a co-dominant genetic model and 1.32 in a recessive genetic model. (PMID:18231128)
• PSMA6 rs_1048990 polymorphism may contribute to MI susceptibility in type 2 diabetes. (PMID:18358479)
• Our results indicate that the PSMA6 variant rs1048990 is a risk factor of myocardial infarction in the Chinese population. (PMID:19272601)
• A total of 1330 cases and 2554 controls from Japanese and Korean populations for PSMA6 genotypes were investigated, and no evidence of the association was obtained in both Japanese and Korean populations. (PMID:19282875)
• Obtained data suggest the LMP2 and PSMA6 gene polymorphisms significance as the risk factors of essential hypertension in adolescents. (PMID:19526842)
• Haplotypes in KIAA0391 and PSMA6 genes is a genetic link for myocardial infarction and coronary artery disease. (PMID:19624571)
• the G-allele of the PSMA6-8C>G polymorphism is a possible survival prognosticator in multiple myeloma (PMID:20408869)
• PSMA6 polymorphisms were not associated with phenotype of coronary atherosclerosis. (PMID:22310064)
• The PSMA6 variant rs1048990 appears to affect susceptibility to ischaemic stroke in both caucasian and african american populations. (PMID:22882272)
• Investigation suggests that -8 C/G variant of PSMA6 gene may be associated with T2DM and diabetes-related metabolic traits in Chinese Dongxiang and Han populations. (PMID:23026512)
• The G allele of PSMA6-8C/G polymorphism is a risk factor associated with increased coronary artery disease susceptibility. [Meat-analysis] (PMID:23111455)
• The data show that LMP2 and PSMA6 gene polymorphism is not a risk factor of ischemic stroke in Ukrainian population. (PMID:24809174)
• Evidence of a sex-specific association of PSMA6 genetic variants with subtypes of juvenile idiopathic arthritis. (PMID:24875235)
• Data indicate that proteasome subunit alpha 6 (PSMA6) direct contacts with proteasome subunit alpha 7 (PSMA7) tetradecamer. (PMID:26657688)
• Our results provide evidence on new T1DM-susceptible loci in the PSMA3, PSMA6 and PSMC6 proteasome genes and give a new insight into the T1DM pathogenesis (PMID:26661414)
• These data indicate that hepatic expression of PSMA6, which is upregulated during viral hepatitis, likely depends on TLR3 activation and, that PSMA6 affects the expression of immunoregulatory ISG15, a proviral factor in the pathogenesis of hepatitis C virus infection. (PMID:26833585)
• The 5’ untranslated region of PSMA6 gene contains a single nucleotide polymorphism -8 C/G associated with End-stage kidney disease and might be a protective factor for the disease. (PMID:27671905)
• Results suggest that proteasome subunit alpha type 6 (PSMA6) serves as an attractive target with a high therapeutic index for lung cancer. (PMID:28165654)
• PSMA6 is post-transcriptionally repressed by the microRNA-4490 in diabetic nephropathy. (PMID:30287505)
• Genome-wide CRISPR screen followed by multiple siRNA screens in several pancreatic ductal adenocarcinoma (PDAC) cell models and in a noncancerous cell model validated PSMA6 as gene essential for cancer cells survival and showed that inhibition of this gene induces apoptosis and results in significantly reduced cell viability. Study provide compelling evidence that PSMA6 plays a significant oncogenic role. (PMID:30898113)
• The Impact of the NOD2/CARD15 Variant (3020insC) and PSMA6 Polymorphism (-8C>G) on the Development and Outcome of Multiple Myeloma. (PMID:32596371)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	psma6b	ENSDARG00000013966
danio_rerio	psma6a	ENSDARG00000019398
mus_musculus	Psma6	ENSMUSG00000021024
rattus_norvegicus	Psma6	ENSRNOG00000007114
rattus_norvegicus	Psma6-ps5	ENSRNOG00000049150
drosophila_melanogaster	Prosalpha1R	FBGN0050382
drosophila_melanogaster	Prosalpha1	FBGN0263121
caenorhabditis_elegans		WBGENE00003922

Paralogs (18): PSMB1 (ENSG00000008018), PSMA4 (ENSG00000041357), PSMA3 (ENSG00000100567), PSMB5 (ENSG00000100804), PSMA7 (ENSG00000101182), PSMA2 (ENSG00000106588), PSMB2 (ENSG00000126067), PSMA1 (ENSG00000129084), PSMB7 (ENSG00000136930), PSMB6 (ENSG00000142507), PSMA5 (ENSG00000143106), PSMA8 (ENSG00000154611), PSMB4 (ENSG00000159377), PSMB8 (ENSG00000204264), PSMB10 (ENSG00000205220), PSMB11 (ENSG00000222028), PSMB9 (ENSG00000240065), PSMB3 (ENSG00000277791)

Protein

Protein identifiers

Proteasome subunit alpha type-6 — P60900 (reviewed: P60900)

Alternative names: 27 kDa prosomal protein, Macropain iota chain, Multicatalytic endopeptidase complex iota chain, Proteasome iota chain, Proteasome subunit alpha-1

All UniProt accessions (9): P60900, A0A140VK44, G3V295, G3V2S7, G3V3I1, G3V3U4, G3V4S5, G3V5Z7, H0YJC4

UniProt curated annotations — full annotation on UniProt →

Function. Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).

Subunit / interactions. The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Interacts with ALKBH4.

Subcellular location. Cytoplasm. Nucleus.

Similarity. Belongs to the peptidase T1A family.

Isoforms (3)

UniProt ID	Names	Canonical?
P60900-1	1	yes
P60900-2	2
P60900-3	3

RefSeq proteins (4): NP_001269161, NP_001269162, NP_001269163, NP_002782* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000426	Proteasome_asu_N	Domain
IPR001353	Proteasome_sua/b	Family
IPR023332	Proteasome_alpha-type	Family
IPR029055	Ntn_hydrolases_N	Homologous_superfamily
IPR034642	Proteasome_subunit_alpha6	Family
IPR050115	Proteasome_alpha	Family

Pfam: PF00227, PF10584

UniProt features (39 total): strand 17, helix 9, modified residue 6, turn 2, splice variant 2, chain 1, sequence conflict 1, glycosylation site 1

Structure

Experimental structures (PDB)

171 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
5LE5	X-RAY DIFFRACTION	1.8
5LEY	X-RAY DIFFRACTION	1.9
5LF4	X-RAY DIFFRACTION	1.99
5LF1	X-RAY DIFFRACTION	2
5LF7	X-RAY DIFFRACTION	2
8UD9	ELECTRON MICROSCOPY	2.04
5LF6	X-RAY DIFFRACTION	2.07
5LF3	X-RAY DIFFRACTION	2.1
8BZL	X-RAY DIFFRACTION	2.14
5LEZ	X-RAY DIFFRACTION	2.19
5LEX	X-RAY DIFFRACTION	2.2
7AWE	X-RAY DIFFRACTION	2.29
5LF0	X-RAY DIFFRACTION	2.41
7B12	X-RAY DIFFRACTION	2.43
9K53	ELECTRON MICROSCOPY	2.5
9HMN	ELECTRON MICROSCOPY	2.55
4R3O	X-RAY DIFFRACTION	2.6
6RGQ	ELECTRON MICROSCOPY	2.6
9YUZ	ELECTRON MICROSCOPY	2.6
8QYL	ELECTRON MICROSCOPY	2.67
8CVR	ELECTRON MICROSCOPY	2.7
6KWY	ELECTRON MICROSCOPY	2.72
8QYJ	ELECTRON MICROSCOPY	2.73
8QYM	ELECTRON MICROSCOPY	2.73
8USB	ELECTRON MICROSCOPY	2.73
9MBP	ELECTRON MICROSCOPY	2.75
9PDL	ELECTRON MICROSCOPY	2.76
6E5B	X-RAY DIFFRACTION	2.77
7NAN	ELECTRON MICROSCOPY	2.8
8TM6	ELECTRON MICROSCOPY	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P60900-F1	95.96	0.92

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 (6): 17, 63, 64, 102, 104, 159

Glycosylation sites (1): 5

Function

Pathways and Gene Ontology

Reactome pathways

68 pathways

ID	Pathway
R-HSA-1169091	Activation of NF-kappaB in B cells
R-HSA-1234176	Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha
R-HSA-1236974	ER-Phagosome pathway
R-HSA-1236978	Cross-presentation of soluble exogenous antigens (endosomes)
R-HSA-174084	Autodegradation of Cdh1 by Cdh1:APC/C
R-HSA-174113	SCF-beta-TrCP mediated degradation of Emi1
R-HSA-174154	APC/C:Cdc20 mediated degradation of Securin
R-HSA-174178	APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1
R-HSA-174184	Cdc20:Phospho-APC/C mediated degradation of Cyclin A
R-HSA-180534	Vpu mediated degradation of CD4
R-HSA-180585	Vif-mediated degradation of APOBEC3G
R-HSA-187577	SCF(Skp2)-mediated degradation of p27/p21
R-HSA-195253	Degradation of beta-catenin by the destruction complex
R-HSA-202424	Downstream TCR signaling
R-HSA-211733	Regulation of activated PAK-2p34 by proteasome mediated degradation
R-HSA-2467813	Separation of Sister Chromatids
R-HSA-2871837	FCERI mediated NF-kB activation
R-HSA-349425	Autodegradation of the E3 ubiquitin ligase COP1
R-HSA-350562	Regulation of ornithine decarboxylase (ODC)
R-HSA-382556	ABC-family protein mediated transport
R-HSA-450408	AUF1 (hnRNP D0) binds and destabilizes mRNA
R-HSA-4608870	Asymmetric localization of PCP proteins
R-HSA-4641257	Degradation of AXIN
R-HSA-4641258	Degradation of DVL
R-HSA-5358346	Hedgehog ligand biogenesis
R-HSA-5362768	Hh mutants are degraded by ERAD
R-HSA-5607761	Dectin-1 mediated noncanonical NF-kB signaling
R-HSA-5607764	CLEC7A (Dectin-1) signaling
R-HSA-5610780	Degradation of GLI1 by the proteasome
R-HSA-5610783	Degradation of GLI2 by the proteasome

MSigDB gene sets: 508 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, REACTOME_DNA_REPLICATION, REACTOME_SIGNALING_BY_NOTCH, REACTOME_APC_C_CDH1_MEDIATED_DEGRADATION_OF_CDC20_AND_OTHER_APC_C_CDH1_TARGETED_PROTEINS_IN_LATE_MITOSIS_EARLY_G1, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, WHITEHURST_PACLITAXEL_SENSITIVITY, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, KEGG_PROTEASOME, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_T_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE

GO Biological Process (5): positive regulation of canonical NF-kappaB signal transduction (GO:0043123), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), regulation of inflammatory response (GO:0050727), obsolete proteolysis involved in protein catabolic process (GO:0051603), ubiquitin-dependent protein catabolic process (GO:0006511)

GO Molecular Function (5): RNA binding (GO:0003723), endopeptidase activity (GO:0004175), purine ribonucleoside triphosphate binding (GO:0035639), NF-kappaB binding (GO:0051059), protein binding (GO:0005515)

GO Cellular Component (23): proteasome complex (GO:0000502), P-body (GO:0000932), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), centriole (GO:0005814), cytosol (GO:0005829), proteasome core complex (GO:0005839), ribosome (GO:0005840), cilium (GO:0005929), nuclear matrix (GO:0016363), proteasome core complex, alpha-subunit complex (GO:0019773), myofibril (GO:0030016), sarcomere (GO:0030017), perinuclear theca (GO:0033011), extracellular exosome (GO:0070062), sperm midpiece (GO:0097225), sperm principal piece (GO:0097228), sperm end piece (GO:0097229), ciliary tip (GO:0097542), sperm head-tail coupling apparatus (GO:0120212), sperm glycocalyx (GO:0120238)

Reactome top-level categories

Rollup of top-18 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	8
intracellular protein-containing complex	3
sperm flagellum	3
intracellular membrane-bounded organelle	2
nuclear lumen	2
cytoplasm	2
intracellular membraneless organelle	2
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
inflammatory response	1
regulation of defense response	1
regulation of response to external stimulus	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
nucleic acid binding	1
peptidase activity	1
anion binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
RNA polymerase II-specific DNA-binding transcription factor binding	1
binding	1
endopeptidase complex	1
cytoplasmic ribonucleoprotein granule	1
intracellular anatomical structure	1
microtubule organizing center	1
proteasome complex	1
catalytic complex	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1
proteasome core complex	1
contractile muscle fiber	1
myofibril	1
cytoskeleton	1
perinuclear region of cytoplasm	1
extracellular vesicle	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

281 interactions, top by confidence:

A	B	Type	Score
PSMA1	PSMA7	psi-mi:“MI:0915”(physical association)	0.950
PSMA1	PSMA7	psi-mi:“MI:0914”(association)	0.950
PSMA2	PSMA7	psi-mi:“MI:0914”(association)	0.850
PSMA6	PSMA7	psi-mi:“MI:0915”(physical association)	0.850
PSMA7	PSMA6	psi-mi:“MI:0915”(physical association)	0.850
PSMA3	PSMA6	psi-mi:“MI:0915”(physical association)	0.840
PSMA6	PSMA3	psi-mi:“MI:0915”(physical association)	0.840
UCHL5	PSMD11	psi-mi:“MI:0914”(association)	0.840
PSMA5	PSMA7	psi-mi:“MI:0914”(association)	0.800
PSMB7	PSMA7	psi-mi:“MI:0914”(association)	0.790
PSMB2	PSMD11	psi-mi:“MI:0914”(association)	0.730

BioGRID (629): PSMA6 (Affinity Capture-MS), PSMA6 (Two-hybrid), CADM1 (Two-hybrid), ZBTB44 (Two-hybrid), TRIM39 (Two-hybrid), C19orf57 (Two-hybrid), LIMD2 (Two-hybrid), RNF170 (Two-hybrid), KRTAP4-2 (Two-hybrid), RTP5 (Two-hybrid), PSMA6 (Affinity Capture-MS), PSMA6 (Affinity Capture-MS), PSMA6 (Affinity Capture-MS), PSMA6 (Affinity Capture-MS), PSMA6 (Affinity Capture-Western)

ESM2 similar proteins: A2YXU2, A2Z3I9, O13268, O14818, O16811, O17586, O23715, O24030, O24362, O24616, O48551, O70435, O81146, O94517, P18422, P21243, P22769, P25788, P30186, P34120, P40303, P48004, P52428, P60900, P60901, P90513, Q0J006, Q10329, Q24178, Q27563, Q2YDE4, Q3ZBG0, Q4R7D9, Q58DU5, Q5RDH8, Q6YT00, Q8TAA3, Q95005, Q9CWH6, Q9LSU0

Diamond homologs: A2Y9X7, A2YXU2, A2Z3I9, A3CW55, A4FZT6, A4YCU9, A5UJS2, A6URN9, A6VIP0, A7I9C7, A9A846, B6YSH9, B8GEZ3, C3MQ43, C3MVG1, C3N5R0, C3NEC6, C3NHC6, C4KHD9, C5A2C2, C6A459, F4JJE5, O13268, O14818, O24030, O24616, O24733, O26782, O29760, O59219, O70435, O81148, O81149, O82530, P0C8Y9, P0DKK3, P0DKK4, P18053, P18422, P21670

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
PSMA6	“form complex”	“26S Proteasome”	binding
PSMA6	“down-regulates quantity by destabilization”	XBP1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 121 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
Antigen processing: Ub, ATP-independent proteasomal degradation	13	83.4×	9e-23
Regulation of activated PAK-2p34 by proteasome mediated degradation	22	68.8×	2e-35
Cross-presentation of soluble exogenous antigens (endosomes)	24	68.4×	7e-38
Regulation of ornithine decarboxylase (ODC)	22	67.2×	4e-35
Vpu mediated degradation of CD4	22	65.7×	6e-35
Autodegradation of the E3 ubiquitin ligase COP1	22	65.7×	6e-35
Ubiquitin-dependent degradation of Cyclin D	22	65.7×	6e-35
Vif-mediated degradation of APOBEC3G	23	65.6×	6e-36

GO biological processes:

GO term	Partners	Fold	FDR
proteasome-mediated ubiquitin-dependent protein catabolic process	34	17.2×	4e-30
protein K48-linked ubiquitination	6	9.8×	7e-03
ubiquitin-dependent protein catabolic process	12	8.7×	6e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
2685482	GRCh37/hg19 14q13.1-13.3(chr14:34585231-37477843)x1	Pathogenic

SpliceAI

1079 predictions. Top by Δscore:

Variant	Effect	Δscore
14:35292548:AGTAG:A	donor_loss	1.0000
14:35292549:GTAG:G	donor_gain	1.0000
14:35292552:GGTG:G	donor_loss	1.0000
14:35308089:G:GG	donor_gain	1.0000
14:35308904:T:TA	acceptor_gain	1.0000
14:35308909:ATTAG:A	acceptor_gain	1.0000
14:35308910:TTA:T	acceptor_loss	1.0000
14:35308911:TA:T	acceptor_loss	1.0000
14:35308911:TAGG:T	acceptor_loss	1.0000
14:35308912:A:AG	acceptor_gain	1.0000
14:35308912:AG:A	acceptor_gain	1.0000
14:35308913:G:GG	acceptor_gain	1.0000
14:35308913:G:GT	acceptor_gain	1.0000
14:35308913:GG:G	acceptor_gain	1.0000
14:35308913:GGAC:G	acceptor_gain	1.0000
14:35308913:GGACA:G	acceptor_gain	1.0000
14:35308992:ACAG:A	donor_loss	1.0000
14:35308992:ACAGG:A	donor_loss	1.0000
14:35308993:CAGG:C	donor_loss	1.0000
14:35308996:G:GA	donor_loss	1.0000
14:35308997:T:G	donor_loss	1.0000
14:35310730:A:AG	acceptor_gain	1.0000
14:35310730:AT:A	acceptor_gain	1.0000
14:35310731:T:TA	acceptor_gain	1.0000
14:35310736:T:G	acceptor_gain	1.0000
14:35310737:A:AG	acceptor_gain	1.0000
14:35310737:AAGCT:A	acceptor_gain	1.0000
14:35310738:A:G	acceptor_gain	1.0000
14:35310891:TTGTT:T	donor_gain	1.0000
14:35310892:TGTTG:T	donor_loss	1.0000

AlphaMissense

1612 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:35292501:T:C	F9L	1.000
14:35292502:T:G	F9C	1.000
14:35292503:T:A	F9L	1.000
14:35292503:T:G	F9L	1.000
14:35292504:G:A	D10N	1.000
14:35292504:G:C	D10H	1.000
14:35292504:G:T	D10Y	1.000
14:35292505:A:C	D10A	1.000
14:35292505:A:T	D10V	1.000
14:35292508:G:C	R11P	1.000
14:35292517:C:T	T14I	1.000
14:35292520:T:A	I15N	1.000
14:35292522:T:A	F16I	1.000
14:35292522:T:C	F16L	1.000
14:35292522:T:G	F16V	1.000
14:35292523:T:C	F16S	1.000
14:35292523:T:G	F16C	1.000
14:35292524:T:A	F16L	1.000
14:35292524:T:G	F16L	1.000
14:35292534:G:A	G20S	1.000
14:35292534:G:C	G20R	1.000
14:35292534:G:T	G20C	1.000
14:35292535:G:A	G20D	1.000
14:35292535:G:T	G20V	1.000
14:35292538:G:C	R21P	1.000
14:35292541:T:A	L22H	1.000
14:35292541:T:C	L22P	1.000
14:35292543:T:G	Y23D	1.000
14:35292548:A:C	Q24H	1.000
14:35292548:A:T	Q24H	1.000

dbSNP variants (sampled 300 via entrez): RS1000166711 (14:35308491 A>G), RS1000196977 (14:35317094 G>A,C), RS1000231571 (14:35298264 T>C,G), RS1000270441 (14:35316711 G>C), RS1000284324 (14:35310092 T>C), RS1000291144 (14:35292228 A>G), RS1000783542 (14:35311799 A>G), RS1000795896 (14:35281304 T>A), RS1000832486 (14:35299374 G>A), RS1000854013 (14:35297903 G>A), RS1000910538 (14:35280908 G>A,T), RS1000932657 (14:35305780 T>G), RS1000970989 (14:35299409 G>C), RS1001031030 (14:35292840 C>G,T), RS1001138034 (14:35287108 A>G,T)

Disease associations

OMIM: gene MIM:602855 | disease phenotypes: MIM:608446

GenCC curated gene-disease

Mondo (1): myocardial infarction, susceptibility to (MONDO:0012039)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST000834_5	Psoriasis	2.000000e-08
GCST002874_10	Psoriasis	2.000000e-10
GCST002874_49	Psoriasis	3.000000e-06
GCST002874_51	Psoriasis	5.000000e-06
GCST005038_84	Allergic disease (asthma, hay fever or eczema)	1.000000e-08
GCST006014_22	Creatine kinase levels	3.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004534	creatine kinase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2364701 (PROTEIN COMPLEX), CHEMBL3831201 (PROTEIN COMPLEX GROUP), CHEMBL6067562 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

6 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 43,258 (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
CHEMBL325041	BORTEZOMIB	4	13,120
CHEMBL451887	CARFILZOMIB	4	12,508
CHEMBL2141296	IXAZOMIB	3	6,022
CHEMBL371405	MARIZOMIB	3	7,332
CHEMBL2103884	OPROZOMIB	2	2,738
CHEMBL1232461	MOLIBRESIB	2	1,538

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

Binding affinities (BindingDB)

5 measured of 13 human assays (13 total across all organisms); most potent 5 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(chloropromazine) [3-(2-Chloro-phenothiazin-10-yl)-propyl]-dimethyl-amine	KI	480 nM
(Thioridazine)10-[2-(1-Methyl-piperidin-2-yl)-ethyl]-2-methylsulfanyl-10H-phenothiazine	IC50	3430 nM	US-9504692: Selective inhibition of MALT1 protease by phenothiazine derivatives
N,N-dimethyl-3-[2-(trifluoromethyl)-10-phenothiazinyl]-1-propanamine;hydrochloride	EC50	7800 nM
1-methyl-3-(9H-thioxanthen-9-ylmethyl)piperidine;hydrate;hydrochloride	EC50	11900 nM
3-(2-chloranyl-5,6-dihydrobenzo[b][1]benzazepin-11-yl)-N,N-dimethyl-propan-1-amine;hydrochloride	EC50	12400 nM

ChEMBL bioactivities

317 potent at pChembl≥5 of 341 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.22	IC50	0.6	nM	CINNABARAMIDE G
9.22	Ki	0.6	nM	CHEMBL5624541
9.22	Ki	0.6	nM	BORTEZOMIB
9.04	IC50	0.92	nM	CHEMBL4102324
9.00	IC50	1	nM	CINNABARAMIDE A
8.89	IC50	1.3	nM	MARIZOMIB
8.82	IC50	1.5	nM	CHEMBL4460323
8.70	IC50	2	nM	CHEMBL307387
8.66	IC50	2.2	nM	CHEMBL5419917
8.62	IC50	2.4	nM	CHEMBL4517600
8.62	IC50	2.4	nM	BORTEZOMIB
8.62	IC50	2.4	nM	CHEMBL5413513
8.60	IC50	2.5	nM	CHEMBL4587036
8.59	IC50	2.56	nM	BORTEZOMIB
8.57	IC50	2.7	nM	CHEMBL3237863
8.57	IC50	2.7	nM	CHEMBL5394365
8.52	IC50	3	nM	BORTEZOMIB
8.47	IC50	3.4	nM	CHEMBL4444107
8.47	IC50	3.4	nM	CHEMBL6143686
8.46	IC50	3.43	nM	CHEMBL5197285
8.44	IC50	3.6	nM	CHEMBL4541038
8.41	IC50	3.9	nM	CHEMBL3237862
8.41	IC50	3.9	nM	CHEMBL4547405
8.40	IC50	4	nM	CHEMBL5406440
8.39	IC50	4.1	nM	CHEMBL3237864
8.39	IC50	4.1	nM	CHEMBL3237867
8.39	IC50	4.03	nM	CHEMBL5171225
8.37	IC50	4.28	nM	CHEMBL4581126
8.34	IC50	4.6	nM	CHEMBL4542373
8.34	IC50	4.6	nM	CHEMBL4558648
8.32	IC50	4.8	nM	CHEMBL3237873
8.32	IC50	4.8	nM	CHEMBL4467618
8.30	IC50	5	nM	CHEMBL5398681
8.29	IC50	5.1	nM	CHEMBL3237865
8.29	IC50	5.15	nM	CHEMBL5186240
8.28	IC50	5.2	nM	CHEMBL5429323
8.28	IC50	5.2	nM	CHEMBL5431451
8.25	IC50	5.6	nM	CHEMBL5423645
8.24	IC50	5.7	nM	CHEMBL3237866
8.24	IC50	5.7	nM	CHEMBL3237860
8.23	IC50	5.9	nM	CHEMBL3237868
8.22	IC50	6	nM	CINNABARAMIDE F
8.22	IC50	6	nM	CHEMBL5412037
8.22	IC50	6	nM	CHEMBL74336
8.20	IC50	6.3	nM	CHEMBL5440712
8.19	IC50	6.4	nM	CHEMBL4447701
8.19	IC50	6.4	nM	CHEMBL4435814
8.19	IC50	6.5	nM	CHEMBL4436430
8.19	IC50	6.5	nM	IXAZOMIB
8.16	IC50	6.91	nM	BORTEZOMIB

PubChem BioAssay actives

288 with measured affinity, of 834 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
methyl (2R)-2-acetamido-3-[(2R,3S,4R)-2-[(S)-[(1S)-cyclohex-2-en-1-yl]-hydroxymethyl]-4-hexyl-3-hydroxy-3-methyl-5-oxopyrrolidine-2-carbonyl]sulfanylpropanoate	277357: Inhibition of human 20S proteasome	ic50	0.0006	uM
[(1R)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]-(pyrazine-2-carbonyl)amino]-3-methylbutyl]boronic acid	2131634: Binding affinity to 20s proteosome (unknown origin) assessed as inhibition constant	ki	0.0006	uM
1-N-[(2S)-1-[[(2S)-1-[(2-chlorophenyl)methylamino]-1-oxo-4-phenylbutan-2-yl]amino]-4-(2,2-dimethylpropylamino)-1,4-dioxobutan-2-yl]-4-N-(1,3-thiazol-2-yl)piperidine-1,4-dicarboxamide	1903224: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-Leu Leu-Val-Tyr-AMC as substrate preincubated for 15 mins followed by substrate addition measured by fluorescence assay	ic50	0.0009	uM
(1R,4R,5S)-1-[(S)-[(1S)-cyclohex-2-en-1-yl]-hydroxymethyl]-4-hexyl-5-methyl-6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione	277357: Inhibition of human 20S proteasome	ic50	0.0010	uM
(1R,4R,5S)-4-(2-chloroethyl)-1-[(S)-[(1S)-cyclohex-2-en-1-yl]-hydroxymethyl]-5-methyl-6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione	1853759: Inhibition of 20S proteasome (unknown origin) by fluorescence based assay	ic50	0.0013	uM
1-N-[(2S)-4-methyl-1-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopentan-2-yl]-4-N-(1,3-thiazol-2-yl)piperidine-1,4-dicarboxamide	1624025: Inhibition of human 20S proteasome preincubated for 15 mins followed by substrate addition	ic50	0.0015	uM
N-[5-[[amino(nitramido)methylidene]amino]-1-[(4-methyl-1-oxopentan-2-yl)amino]-1-oxopentan-2-yl]-2-cyclopentyl-10-(1,3-dioxoisoindol-2-yl)decanamide	3028: Compound was evaluated for inhibitory activity against 20S proteasome from human liver and brain	ic50	0.0020	uM
4-[(1R)-1-[[2-[[2,5-bis(trifluoromethyl)benzoyl]amino]-3-cyclopropylpropanoyl]amino]-3-methylbutyl]-2-methyl-3,5,10-trioxa-4-boratricyclo[5.2.1.02,6]decane-8-carboxylic acid	2033891: Inhibition of human 20S proteasome chymotrypsin-like activity using Suc-Leu-Leu-Val-Tyr-AMC as fluorogenic peptide pre-incubated for 10 mins with compound followed by substrate addition for 60 mins by spectrofluorimetric analysis	ic50	0.0022	uM
4-N-(4-benzoylphenyl)-1-N-[(2S)-4-methyl-1-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopentan-2-yl]piperidine-1,4-dicarboxamide	1624025: Inhibition of human 20S proteasome preincubated for 15 mins followed by substrate addition	ic50	0.0024	uM
4-[(1R)-1-[[2-[[2,5-bis(trifluoromethyl)benzoyl]amino]-2-cyclopentylacetyl]amino]-3-methylbutyl]-2-methyl-3,5,10-trioxa-4-boratricyclo[5.2.1.02,6]decane-8-carboxylic acid	2033891: Inhibition of human 20S proteasome chymotrypsin-like activity using Suc-Leu-Leu-Val-Tyr-AMC as fluorogenic peptide pre-incubated for 10 mins with compound followed by substrate addition for 60 mins by spectrofluorimetric analysis	ic50	0.0024	uM
Bortezomib	1985684: Inhibition of 26S proteasome (unknown origin)	ic50	0.0024	uM
(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-acetamido-3-(4-hydroxyphenyl)propanoyl]amino]acetyl]amino]-5-carbamimidamidopentanoyl]amino]-6-aminohexanoyl]amino]-6-aminohexanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-N-[(2S)-5-carbamimidamido-1-[[(2S)-5-carbamimidamido-1-[[(2S)-5-carbamimidamido-1-[[2-[[2-[[2-[[(2S)-4-methyl-1-[[(2S)-4-methyl-1-[[(2S)-4-methyl-1-oxopentan-2-yl]amino]-1-oxopentan-2-yl]amino]-1-oxopentan-2-yl]amino]-2-oxoethyl]amino]-2-oxoethyl]amino]-2-oxoethyl]amino]-1-oxopentan-2-yl]amino]-1-oxopentan-2-yl]amino]-1-oxopentan-2-yl]pentanediamide	1559513: Inhibition of human 20S proteasome using Suc-LLVY-AMC as substrate measured every 5 mins for 120 mins by fluorescence based assay	ic50	0.0025	uM
4-[(1R)-1-[[2-[[2,5-bis(trifluoromethyl)benzoyl]amino]-2-cyclopropylacetyl]amino]-3-methylbutyl]-2-methyl-3,5,10-trioxa-4-boratricyclo[5.2.1.02,6]decane-8-carboxylic acid	2033891: Inhibition of human 20S proteasome chymotrypsin-like activity using Suc-Leu-Leu-Val-Tyr-AMC as fluorogenic peptide pre-incubated for 10 mins with compound followed by substrate addition for 60 mins by spectrofluorimetric analysis	ic50	0.0027	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-N-(4-fluorophenyl)-1-N-[(2S)-4-methyl-1-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopentan-2-yl]piperidine-1,4-dicarboxamide	1624025: Inhibition of human 20S proteasome preincubated for 15 mins followed by substrate addition	ic50	0.0034	uM
1-N-[(2S)-4-(2,2-dimethylpropylamino)-1,4-dioxo-1-[[(2S)-1-oxo-4-phenyl-1-[[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]amino]butan-2-yl]amino]butan-2-yl]-4-N-methyl-4-N-(1,3-thiazol-2-yl)piperidine-1,4-dicarboxamide	1903224: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-Leu Leu-Val-Tyr-AMC as substrate preincubated for 15 mins followed by substrate addition measured by fluorescence assay	ic50	0.0034	uM
1-N-[(2S)-4-methyl-1-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopentan-2-yl]-4-N-pyridin-3-ylpiperidine-1,4-dicarboxamide	1624025: Inhibition of human 20S proteasome preincubated for 15 mins followed by substrate addition	ic50	0.0036	uM
4-N-(1,3-benzothiazol-2-yl)-1-N-[(2S)-4-methyl-1-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopentan-2-yl]piperidine-1,4-dicarboxamide	1624025: Inhibition of human 20S proteasome preincubated for 15 mins followed by substrate addition	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’-[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
[(1R)-1-[[2-[(2,5-dibromobenzoyl)amino]acetyl]amino]-3-methylbutyl]boronic acid	2033891: Inhibition of human 20S proteasome chymotrypsin-like activity using Suc-Leu-Leu-Val-Tyr-AMC as fluorogenic peptide pre-incubated for 10 mins with compound followed by substrate addition for 60 mins by spectrofluorimetric analysis	ic50	0.0040	uM
1-N-[(2S)-4-(2,2-dimethylpropylamino)-1,4-dioxo-1-[[(2S)-1-oxo-4-phenyl-1-[[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]amino]butan-2-yl]amino]butan-2-yl]-4-N-pyridin-3-ylpiperidine-1,4-dicarboxamide	1903224: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-Leu Leu-Val-Tyr-AMC as substrate preincubated for 15 mins followed by substrate addition measured by fluorescence assay	ic50	0.0040	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-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-acetamido-3-(4-hydroxyphenyl)propanoyl]amino]acetyl]amino]-5-carbamimidamidopentanoyl]amino]-6-aminohexanoyl]amino]-6-aminohexanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-N-[(2S)-5-carbamimidamido-1-[[(2S)-5-carbamimidamido-1-[[(2S)-5-carbamimidamido-1-[[2-[[2-[[2-[[(2S)-3-(4-hydroxyphenyl)-1-[[(2S)-4-methyl-1-[[(2S)-1-[[(2S)-4-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-2-oxoethyl]amino]-2-oxoethyl]amino]-1-oxopentan-2-yl]amino]-1-oxopentan-2-yl]amino]-1-oxopentan-2-yl]pentanediamide	1559513: Inhibition of human 20S proteasome using Suc-LLVY-AMC as substrate measured every 5 mins for 120 mins by fluorescence based assay	ic50	0.0043	uM
1-N-[(2S)-4-methyl-1-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopentan-2-yl]-4-N-(1,3,4-thiadiazol-2-yl)piperidine-1,4-dicarboxamide	1624025: Inhibition of human 20S proteasome preincubated for 15 mins followed by substrate addition	ic50	0.0046	uM
4-N-(4-chlorophenyl)-1-N-[(2S)-4-methyl-1-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopentan-2-yl]piperidine-1,4-dicarboxamide	1624025: Inhibition of human 20S proteasome preincubated for 15 mins followed by substrate addition	ic50	0.0046	uM
4-N-(4-methoxyphenyl)-1-N-[(2S)-4-methyl-1-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopentan-2-yl]piperidine-1,4-dicarboxamide	1624025: Inhibition of human 20S proteasome preincubated for 15 mins followed by substrate addition	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’-(4-phenylmethoxybutyl)butanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0048	uM
[(1R)-1-[[2-[[2,5-bis(trifluoromethyl)benzoyl]amino]-3-cyclopropylpropanoyl]amino]-3-methylbutyl]boronic acid	2033891: Inhibition of human 20S proteasome chymotrypsin-like activity using Suc-Leu-Leu-Val-Tyr-AMC as fluorogenic peptide pre-incubated for 10 mins with compound followed by substrate addition for 60 mins by spectrofluorimetric analysis	ic50	0.0050	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)-N’-(2,2-dimethylpropyl)-2-[[4-[methyl(pyridine-3-carbonyl)amino]piperidine-1-carbonyl]amino]-N-[(2S)-1-oxo-4-phenyl-1-[[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]amino]butan-2-yl]butanediamide	1903224: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-Leu Leu-Val-Tyr-AMC as substrate preincubated for 15 mins followed by substrate addition measured by fluorescence assay	ic50	0.0052	uM
4-[(1R)-1-[[2-[(2,5-dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]-2-methyl-3,5,10-trioxa-4-boratricyclo[5.2.1.02,6]decane-8-carboxylic acid	2033891: Inhibition of human 20S proteasome chymotrypsin-like activity using Suc-Leu-Leu-Val-Tyr-AMC as fluorogenic peptide pre-incubated for 10 mins with compound followed by substrate addition for 60 mins by spectrofluorimetric analysis	ic50	0.0052	uM
[(1R)-1-[[2-[[2,5-bis(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-methylbutyl]boronic acid	2033891: Inhibition of human 20S proteasome chymotrypsin-like activity using Suc-Leu-Leu-Val-Tyr-AMC as fluorogenic peptide pre-incubated for 10 mins with compound followed by substrate addition for 60 mins by spectrofluorimetric analysis	ic50	0.0052	uM
[(1R)-1-[[2-[[2,5-bis(trifluoromethyl)benzoyl]amino]-2-cyclopropylacetyl]amino]-3-methylbutyl]boronic acid	2033891: Inhibition of human 20S proteasome chymotrypsin-like activity using Suc-Leu-Leu-Val-Tyr-AMC as fluorogenic peptide pre-incubated for 10 mins with compound followed by substrate addition for 60 mins by spectrofluorimetric analysis	ic50	0.0056	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
(2R)-2-acetamido-3-[(2R,3S,4R)-2-[(S)-[(1S)-cyclohex-2-en-1-yl]-hydroxymethyl]-4-hexyl-3-hydroxy-3-methyl-5-oxopyrrolidine-2-carbonyl]sulfanylpropanoic acid	277357: Inhibition of human 20S proteasome	ic50	0.0060	uM
[(1R)-1-[[2-[[2,5-bis(trifluoromethyl)benzoyl]amino]-2-cyclopentylacetyl]amino]-3-methylbutyl]boronic acid	2033891: Inhibition of human 20S proteasome chymotrypsin-like activity using Suc-Leu-Leu-Val-Tyr-AMC as fluorogenic peptide pre-incubated for 10 mins with compound followed by substrate addition for 60 mins by spectrofluorimetric analysis	ic50	0.0060	uM
N-[5-[[amino(nitramido)methylidene]amino]-1-[(4-methyl-1-oxopentan-2-yl)amino]-1-oxopentan-2-yl]-10-cyano-2-cyclopentyldecanamide	3028: Compound was evaluated for inhibitory activity against 20S proteasome from human liver and brain	ic50	0.0060	uM
4-[(1R)-1-[[2-[(2,5-dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]-3,5,10-trioxa-4-boratricyclo[5.2.1.02,6]decane-8-carboxylic acid	2033891: Inhibition of human 20S proteasome chymotrypsin-like activity using Suc-Leu-Leu-Val-Tyr-AMC as fluorogenic peptide pre-incubated for 10 mins with compound followed by substrate addition for 60 mins by spectrofluorimetric analysis	ic50	0.0063	uM
1-N-[(2S)-4-methyl-1-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopentan-2-yl]-4-N-(1,2-oxazol-3-yl)piperidine-1,4-dicarboxamide	1624025: Inhibition of human 20S proteasome preincubated for 15 mins followed by substrate addition	ic50	0.0064	uM
(2S)-2-[[(2S)-2-acetamido-3-(4-hydroxyphenyl)propanoyl]amino]-4-methyl-N-[(2S)-1-[[(2S)-4-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]pentanamide	1559513: Inhibition of human 20S proteasome using Suc-LLVY-AMC as substrate measured every 5 mins for 120 mins by fluorescence based assay	ic50	0.0064	uM
1-N-[(2S)-4-methyl-1-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopentan-2-yl]-4-N-pyrazin-2-ylpiperidine-1,4-dicarboxamide	1624025: Inhibition of human 20S proteasome preincubated for 15 mins followed by substrate addition	ic50	0.0065	uM
Ixazomib	2033891: Inhibition of human 20S proteasome chymotrypsin-like activity using Suc-Leu-Leu-Val-Tyr-AMC as fluorogenic peptide pre-incubated for 10 mins with compound followed by substrate addition for 60 mins by spectrofluorimetric analysis	ic50	0.0065	uM
4-N-(4-chlorophenyl)-1-N-[(2S)-4-(2,2-dimethylpropylamino)-1,4-dioxo-1-[[(2S)-1-oxo-4-phenyl-1-[[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]amino]butan-2-yl]amino]butan-2-yl]-4-N-methylpiperidine-1,4-dicarboxamide	1903224: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-Leu Leu-Val-Tyr-AMC as substrate preincubated for 15 mins followed by substrate addition measured by fluorescence assay	ic50	0.0069	uM
(2S)-N-[(2S,3R,4R)-3-hydroxy-5-[[(2S)-1-[(2-hydroxy-4-methoxyphenyl)methylamino]-3-methyl-1-oxobutan-2-yl]amino]-5-oxo-1-phenyl-4-[(3,4,5-trimethoxyphenyl)methylamino]pentan-2-yl]-3,3-dimethyl-2-[(2-naphthalen-1-ylacetyl)amino]butanamide	3027: Tested in vitro for inhibition of chymotrypsin like activity of purified human 20S proteasome	ic50	0.0070	uM
Carfilzomib	1770085: Inhibition of human 20S proteasome chymotrypsin-like activity in human RPMI-8226 cells using Suc-LLVY-AMC as fluorogenic substrate incubated for 3 hrs by fluorescence assay	ic50	0.0070	uM
(2S)-2-[[(2S)-3-(4-hydroxyphenyl)-2-[(2-naphthalen-1-ylacetyl)amino]propanoyl]amino]-N-[1-(4-hydroxyphenyl)-3-oxopropan-2-yl]-3-methylbutanamide	248827: Inhibitory concentration to inhibit chymotrypsin-like activity of 20S proteasome prepared from human leukemia HL-60 cells was determined	ic50	0.0070	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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression, affects expression	3
Air Pollutants	decreases expression, affects expression, increases abundance	2
aristolochic acid I	increases expression	1
bisphenol F	increases expression	1
nobiletin	decreases reaction, decreases expression	1
sodium arsenate	decreases expression, decreases reaction	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression	1
quercitrin	decreases expression	1
arsenite	affects binding, increases reaction	1
sodium arsenite	affects cotreatment, increases abundance, increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
di-n-butylphosphoric acid	affects expression	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	increases expression	1
CGP 52608	increases reaction, affects binding	1
chloropicrin	increases expression	1
tanespimycin	affects cotreatment, decreases expression	1
K 7174	decreases expression	1
ICG 001	increases expression	1
bisphenol B	increases expression	1
bisphenol S	increases expression	1
VER 155008	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
Resveratrol	increases expression, affects cotreatment	1
Arsenic Trioxide	increases expression	1
Acetaminophen	decreases expression	1
Arsenic	increases abundance, increases expression, affects cotreatment	1
Benzo(a)pyrene	decreases expression	1
Caffeine	affects phosphorylation	1
Doxorubicin	increases metabolic processing	1
Environmental Pollutants	affects expression	1

ChEMBL screening assays

175 unique, capped per target: 166 binding, 6 admet, 3 functional

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
CHEMBL4736581	ADMET	Inhibition of human 20S proteasome stably expressed in HEK293 cells at 5 to 50 uM using succinyl-LLVY-AMC as substrate preincubated for 30 mins followed by substrate addition and measured at 3 mins interval for 30 mins by fluorescence assay	A covalent p97/VCP ATPase inhibitor can overcome resistance to CB-5083 and NMS-873 in colorectal cancer cells. — Eur J Med Chem
CHEMBL834792	Functional	Inhibitory concentration to inhibit trypsin-like activity of 20S proteasome from human leukemia HL-60 cells was determined	Structure-based design of derivatives of tyropeptin A as the potent and selective inhibitors of mammalian 20S proteasome. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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