Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLHD56E)

DOT Name 26S proteasome regulatory subunit 4 (PSMC1)
Synonyms P26s4; 26S proteasome AAA-ATPase subunit RPT2; Proteasome 26S subunit ATPase 1
Gene Name PSMC1
Related Disease
Angiomyolipoma ( )
Ataxia-telangiectasia ( )
Cognitive impairment ( )
Myopia ( )
Status epilepticus seizure ( )
Cervical carcinoma ( )
Neurodevelopmental disorder with poor growth, spastic tetraplegia, and hearing loss ( )
Parkinson disease ( )
UniProt ID
PRS4_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
5GJQ ; 5GJR ; 5L4G ; 5LN3 ; 5M32 ; 5T0C ; 5T0G ; 5T0H ; 5T0I ; 5T0J ; 5VFP ; 5VFQ ; 5VFR ; 5VFS ; 5VFT ; 5VFU ; 5VGZ ; 5VHF ; 5VHH ; 5VHI ; 5VHJ ; 5VHM ; 5VHN ; 5VHO ; 5VHP ; 5VHQ ; 5VHR ; 5VHS ; 6MSB ; 6MSD ; 6MSG ; 6MSH ; 6MSJ ; 6MSK ; 6WJD ; 6WJN ; 7QXN ; 7QXP ; 7QXU ; 7QXW ; 7QXX ; 7QY7 ; 7QYA ; 7QYB ; 7W37 ; 7W38 ; 7W39 ; 7W3A ; 7W3B ; 7W3C ; 7W3F ; 7W3G ; 7W3H ; 7W3I ; 7W3J ; 7W3K ; 7W3M ; 8CVT
Pfam ID
PF00004 ; PF17862 ; PF16450
Sequence
MGQSQSGGHGPGGGKKDDKDKKKKYEPPVPTRVGKKKKKTKGPDAASKLPLVTPHTQCRL
KLLKLERIKDYLLMEEEFIRNQEQMKPLEEKQEEERSKVDDLRGTPMSVGTLEEIIDDNH
AIVSTSVGSEHYVSILSFVDKDLLEPGCSVLLNHKVHAVIGVLMDDTDPLVTVMKVEKAP
QETYADIGGLDNQIQEIKESVELPLTHPEYYEEMGIKPPKGVILYGPPGTGKTLLAKAVA
NQTSATFLRVVGSELIQKYLGDGPKLVRELFRVAEEHAPSIVFIDEIDAIGTKRYDSNSG
GEREIQRTMLELLNQLDGFDSRGDVKVIMATNRIETLDPALIRPGRIDRKIEFPLPDEKT
KKRIFQIHTSRMTLADDVTLDDLIMAKDDLSGADIKAICTEAGLMALRERRMKVTNEDFK
KSKENVLYKKQEGTPEGLYL
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. PSMC1 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.
KEGG Pathway
Proteasome (hsa03050 )
Alzheimer disease (hsa05010 )
Parkinson disease (hsa05012 )
Amyotrophic lateral sclerosis (hsa05014 )
Huntington disease (hsa05016 )
Spinocerebellar ataxia (hsa05017 )
Prion disease (hsa05020 )
Pathways of neurodegeneration - multiple diseases (hsa05022 )
Human papillomavirus infection (hsa05165 )
Epstein-Barr virus infection (hsa05169 )
Viral carcinogenesis (hsa05203 )
Reactome Pathway
Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha (R-HSA-1234176 )
ER-Phagosome pathway (R-HSA-1236974 )
Cross-presentation of soluble exogenous antigens (endosomes) (R-HSA-1236978 )
Autodegradation of Cdh1 by Cdh1 (R-HSA-174084 )
SCF-beta-TrCP mediated degradation of Emi1 (R-HSA-174113 )
APC/C (R-HSA-174154 )
APC/C (R-HSA-174178 )
Cdc20 (R-HSA-174184 )
Vpu mediated degradation of CD4 (R-HSA-180534 )
Vif-mediated degradation of APOBEC3G (R-HSA-180585 )
SCF(Skp2)-mediated degradation of p27/p21 (R-HSA-187577 )
Degradation of beta-catenin by the destruction complex (R-HSA-195253 )
Downstream TCR signaling (R-HSA-202424 )
Regulation of activated PAK-2p34 by proteasome mediated degradation (R-HSA-211733 )
Separation of Sister Chromatids (R-HSA-2467813 )
FCERI mediated NF-kB activation (R-HSA-2871837 )
Autodegradation of the E3 ubiquitin ligase COP1 (R-HSA-349425 )
Regulation of ornithine decarboxylase (ODC) (R-HSA-350562 )
ABC-family proteins mediated transport (R-HSA-382556 )
AUF1 (hnRNP D0) binds and destabilizes mRNA (R-HSA-450408 )
Asymmetric localization of PCP proteins (R-HSA-4608870 )
Degradation of AXIN (R-HSA-4641257 )
Degradation of DVL (R-HSA-4641258 )
N-glycan trimming in the ER and Calnexin/Calreticulin cycle (R-HSA-532668 )
Hedgehog ligand biogenesis (R-HSA-5358346 )
Hh mutants are degraded by ERAD (R-HSA-5362768 )
Dectin-1 mediated noncanonical NF-kB signaling (R-HSA-5607761 )
CLEC7A (Dectin-1) signaling (R-HSA-5607764 )
Degradation of GLI1 by the proteasome (R-HSA-5610780 )
Degradation of GLI2 by the proteasome (R-HSA-5610783 )
GLI3 is processed to GLI3R by the proteasome (R-HSA-5610785 )
Hedgehog 'on' state (R-HSA-5632684 )
Regulation of RAS by GAPs (R-HSA-5658442 )
TNFR2 non-canonical NF-kB pathway (R-HSA-5668541 )
NIK-->noncanonical NF-kB signaling (R-HSA-5676590 )
Defective CFTR causes cystic fibrosis (R-HSA-5678895 )
MAPK6/MAPK4 signaling (R-HSA-5687128 )
UCH proteinases (R-HSA-5689603 )
Ub-specific processing proteases (R-HSA-5689880 )
Assembly of the pre-replicative complex (R-HSA-68867 )
Orc1 removal from chromatin (R-HSA-68949 )
CDK-mediated phosphorylation and removal of Cdc6 (R-HSA-69017 )
G2/M Checkpoints (R-HSA-69481 )
Ubiquitin Mediated Degradation of Phosphorylated Cdc25A (R-HSA-69601 )
Ubiquitin-dependent degradation of Cyclin D (R-HSA-75815 )
The role of GTSE1 in G2/M progression after G2 checkpoint (R-HSA-8852276 )
FBXL7 down-regulates AURKA during mitotic entry and in early mitosis (R-HSA-8854050 )
RUNX1 regulates transcription of genes involved in differentiation of HSCs (R-HSA-8939236 )
Regulation of RUNX2 expression and activity (R-HSA-8939902 )
Regulation of RUNX3 expression and activity (R-HSA-8941858 )
Regulation of PTEN stability and activity (R-HSA-8948751 )
Neddylation (R-HSA-8951664 )
Regulation of expression of SLITs and ROBOs (R-HSA-9010553 )
Interleukin-1 signaling (R-HSA-9020702 )
Negative regulation of NOTCH4 signaling (R-HSA-9604323 )
KEAP1-NFE2L2 pathway (R-HSA-9755511 )
GSK3B and BTRC (R-HSA-9762114 )
Somitogenesis (R-HSA-9824272 )
Antigen processing (R-HSA-983168 )
Activation of NF-kappaB in B cells (R-HSA-1169091 )

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Angiomyolipoma DIS2L71N Strong Biomarker [1]
Ataxia-telangiectasia DISP3EVR Strong Biomarker [2]
Cognitive impairment DISH2ERD Strong Biomarker [3]
Myopia DISK5S60 Strong Biomarker [4]
Status epilepticus seizure DISY3BIC Strong Genetic Variation [5]
Cervical carcinoma DIST4S00 moderate Biomarker [6]
Neurodevelopmental disorder with poor growth, spastic tetraplegia, and hearing loss DISMDYRI Limited Autosomal recessive [7]
Parkinson disease DISQVHKL Limited Biomarker [8]
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⏷ Show the Full List of 8 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
11 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Doxorubicin DMVP5YE Approved Doxorubicin affects the expression of 26S proteasome regulatory subunit 4 (PSMC1). [9]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate increases the expression of 26S proteasome regulatory subunit 4 (PSMC1). [10]
Ivermectin DMDBX5F Approved Ivermectin decreases the expression of 26S proteasome regulatory subunit 4 (PSMC1). [11]
Selenium DM25CGV Approved Selenium increases the expression of 26S proteasome regulatory subunit 4 (PSMC1). [12]
Benzatropine DMF7EXL Approved Benzatropine decreases the expression of 26S proteasome regulatory subunit 4 (PSMC1). [13]
Tocopherol DMBIJZ6 Phase 2 Tocopherol increases the expression of 26S proteasome regulatory subunit 4 (PSMC1). [12]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 decreases the expression of 26S proteasome regulatory subunit 4 (PSMC1). [15]
MG-132 DMKA2YS Preclinical MG-132 increases the expression of 26S proteasome regulatory subunit 4 (PSMC1). [16]
[3H]methyltrienolone DMTSGOW Investigative [3H]methyltrienolone increases the expression of 26S proteasome regulatory subunit 4 (PSMC1). [18]
Aminohippuric acid DMUN54G Investigative Aminohippuric acid affects the expression of 26S proteasome regulatory subunit 4 (PSMC1). [19]
Flavone DMEQH6J Investigative Flavone increases the expression of 26S proteasome regulatory subunit 4 (PSMC1). [20]
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⏷ Show the Full List of 11 Drug(s)
2 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
TAK-243 DM4GKV2 Phase 1 TAK-243 decreases the sumoylation of 26S proteasome regulatory subunit 4 (PSMC1). [14]
Bisphenol A DM2ZLD7 Investigative Bisphenol A increases the methylation of 26S proteasome regulatory subunit 4 (PSMC1). [17]
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References

1 Mutation in TSC2 and activation of mammalian target of rapamycin signalling pathway in renal angiomyolipoma.Lancet. 2003 Apr 19;361(9366):1348-9. doi: 10.1016/S0140-6736(03)13044-9.
2 Rapid flow cytometry-based structural maintenance of chromosomes 1 (SMC1) phosphorylation assay for identification of ataxia-telangiectasia homozygotes and heterozygotes.Clin Chem. 2009 Mar;55(3):463-72. doi: 10.1373/clinchem.2008.107128. Epub 2009 Jan 15.
3 Key role of soluble epoxide hydrolase in the neurodevelopmental disorders of offspring after maternal immune activation.Proc Natl Acad Sci U S A. 2019 Apr 2;116(14):7083-7088. doi: 10.1073/pnas.1819234116. Epub 2019 Mar 19.
4 Genetic deletion of the adenosine A2A receptor confers postnatal development of relative myopia in mice.Invest Ophthalmol Vis Sci. 2010 Sep;51(9):4362-70. doi: 10.1167/iovs.09-3998. Epub 2010 May 19.
5 Altered Synaptic Drive onto Birthdated Dentate Granule Cells in Experimental Temporal Lobe Epilepsy.J Neurosci. 2019 Sep 18;39(38):7604-7614. doi: 10.1523/JNEUROSCI.0654-18.2019. Epub 2019 Jul 3.
6 Identification of a promoter in position 56 within the long control region of human papillomavirus type 18.Arch Virol. 2001;146(11):2069-84. doi: 10.1007/s007050170021.
7 Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
8 PSMC1 Gene in Parkinson's Disease.Eur Neurol. 2012;68(4):193-8. doi: 10.1159/000339003. Epub 2012 Aug 29.
9 Expression Profiling of Human Pluripotent Stem Cell-Derived Cardiomyocytes Exposed to Doxorubicin-Integration and Visualization of Multi-Omics Data. Toxicol Sci. 2018 May 1;163(1):182-195. doi: 10.1093/toxsci/kfy012.
10 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
11 Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
12 Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
13 Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
14 Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
15 Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
16 Proteasome inhibition creates a chromatin landscape favorable to RNA Pol II processivity. J Biol Chem. 2020 Jan 31;295(5):1271-1287. doi: 10.1074/jbc.RA119.011174. Epub 2019 Dec 5.
17 DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
18 Evaluation of an in vitro model of androgen ablation and identification of the androgen responsive proteome in LNCaP cells. Proteomics. 2007 Jan;7(1):47-63.
19 Identification of molecular signatures predicting the carcinogenicity of polycyclic aromatic hydrocarbons (PAHs). Toxicol Lett. 2012 Jul 7;212(1):18-28. doi: 10.1016/j.toxlet.2012.04.013. Epub 2012 May 1.
20 Identification of biomarkers for the initiation of apoptosis in human preneoplastic colonocytes by proteome analysis. Int J Cancer. 2004 Mar 20;109(2):220-9. doi: 10.1002/ijc.11692.