Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS3XN41)

DOT Name 26S proteasome regulatory subunit 6B (PSMC4)
Synonyms 26S proteasome AAA-ATPase subunit RPT3; MB67-interacting protein; MIP224; Proteasome 26S subunit ATPase 4; Tat-binding protein 7; TBP-7
Gene Name PSMC4
Related Disease
Adenoma ( )
Breast neoplasm ( )
Neoplasm ( )
Parkinson disease ( )
UniProt ID
PRS6B_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
2DVW ; 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 ; 6MSE ; 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
MEEIGILVEKAQDEIPALSVSRPQTGLSFLGPEPEDLEDLYSRYKKLQQELEFLEVQEEY
IKDEQKNLKKEFLHAQEEVKRIQSIPLVIGQFLEAVDQNTAIVGSTTGSNYYVRILSTID
RELLKPNASVALHKHSNALVDVLPPEADSSIMMLTSDQKPDVMYADIGGMDIQKQEVREA
VELPLTHFELYKQIGIDPPRGVLMYGPPGCGKTMLAKAVAHHTTAAFIRVVGSEFVQKYL
GEGPRMVRDVFRLAKENAPAIIFIDEIDAIATKRFDAQTGADREVQRILLELLNQMDGFD
QNVNVKVIMATNRADTLDPALLRPGRLDRKIEFPLPDRRQKRLIFSTITSKMNLSEEVDL
EDYVARPDKISGADINSICQESGMLAVRENRYIVLAKDFEKAYKTVIKKDEQEHEFYK
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. PSMC4 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 )
Epstein-Barr virus infection (hsa05169 )
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 )
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

4 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Adenoma DIS78ZEV Strong Biomarker [1]
Breast neoplasm DISNGJLM Strong Altered Expression [2]
Neoplasm DISZKGEW Strong Posttranslational Modification [3]
Parkinson disease DISQVHKL Strong Biomarker [4]
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Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
16 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate increases the expression of 26S proteasome regulatory subunit 6B (PSMC4). [5]
Ciclosporin DMAZJFX Approved Ciclosporin decreases the expression of 26S proteasome regulatory subunit 6B (PSMC4). [6]
Acetaminophen DMUIE76 Approved Acetaminophen decreases the expression of 26S proteasome regulatory subunit 6B (PSMC4). [7]
Doxorubicin DMVP5YE Approved Doxorubicin affects the expression of 26S proteasome regulatory subunit 6B (PSMC4). [8]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate increases the expression of 26S proteasome regulatory subunit 6B (PSMC4). [9]
Ivermectin DMDBX5F Approved Ivermectin decreases the expression of 26S proteasome regulatory subunit 6B (PSMC4). [10]
Arsenic trioxide DM61TA4 Approved Arsenic trioxide increases the expression of 26S proteasome regulatory subunit 6B (PSMC4). [11]
Selenium DM25CGV Approved Selenium increases the expression of 26S proteasome regulatory subunit 6B (PSMC4). [12]
Cannabidiol DM0659E Approved Cannabidiol increases the expression of 26S proteasome regulatory subunit 6B (PSMC4). [13]
Bortezomib DMNO38U Approved Bortezomib increases the expression of 26S proteasome regulatory subunit 6B (PSMC4). [14]
Epigallocatechin gallate DMCGWBJ Phase 3 Epigallocatechin gallate increases the expression of 26S proteasome regulatory subunit 6B (PSMC4). [15]
Tocopherol DMBIJZ6 Phase 2 Tocopherol increases the expression of 26S proteasome regulatory subunit 6B (PSMC4). [12]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene decreases the expression of 26S proteasome regulatory subunit 6B (PSMC4). [16]
PMID28870136-Compound-52 DMFDERP Patented PMID28870136-Compound-52 increases the expression of 26S proteasome regulatory subunit 6B (PSMC4). [15]
MG-132 DMKA2YS Preclinical MG-132 increases the expression of 26S proteasome regulatory subunit 6B (PSMC4). [17]
Bisphenol A DM2ZLD7 Investigative Bisphenol A affects the expression of 26S proteasome regulatory subunit 6B (PSMC4). [18]
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⏷ Show the Full List of 16 Drug(s)

References

1 Selection and validation of reliable reference genes for RT-qPCR analysis in a large cohort of pituitary adenomas.Mol Cell Endocrinol. 2016 Dec 5;437:183-189. doi: 10.1016/j.mce.2016.08.030. Epub 2016 Aug 22.
2 Statistical modeling for selecting housekeeper genes.Genome Biol. 2004;5(8):R59. doi: 10.1186/gb-2004-5-8-r59. Epub 2004 Jul 29.
3 Site-specific proteasome phosphorylation controls cell proliferation and tumorigenesis.Nat Cell Biol. 2016 Feb;18(2):202-12. doi: 10.1038/ncb3289. Epub 2015 Dec 14.
4 Psychotropics regulate Skp1a, Aldh1a1, and Hspa8 transcription--potential to delay Parkinson's disease.Prog Neuropsychopharmacol Biol Psychiatry. 2013 Jan 10;40:236-9. doi: 10.1016/j.pnpbp.2012.08.021. Epub 2012 Oct 7.
5 Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
6 Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
7 Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
8 Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
9 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
10 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.
11 A comprehensive analysis of Wnt/beta-catenin signaling pathway-related genes and crosstalk pathways in the treatment of As2O3 in renal cancer. Ren Fail. 2018 Nov;40(1):331-339.
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 Gingival Stromal Cells as an In Vitro Model: Cannabidiol Modulates Genes Linked With Amyotrophic Lateral Sclerosis. J Cell Biochem. 2017 Apr;118(4):819-828. doi: 10.1002/jcb.25757. Epub 2016 Nov 28.
14 The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
15 Comparative proteomics reveals concordant and discordant biochemical effects of caffeine versus epigallocatechin-3-gallate in human endothelial cells. Toxicol Appl Pharmacol. 2019 Sep 1;378:114621. doi: 10.1016/j.taap.2019.114621. Epub 2019 Jun 10.
16 Benzo(a)pyrene exposure in utero exacerbates Parkinson's Disease (PD)-like -synucleinopathy in A53T human alpha-synuclein transgenic mice. Toxicol Appl Pharmacol. 2021 Sep 15;427:115658. doi: 10.1016/j.taap.2021.115658. Epub 2021 Jul 29.
17 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.
18 Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.