Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6HZHN7)

• DOT Name: 26S proteasome non-ATPase regulatory subunit 2 (PSMD2)
• Synonyms: 26S proteasome regulatory subunit RPN1; 26S proteasome regulatory subunit S2; 26S proteasome subunit p97; Protein 55.11; Tumor necrosis factor type 1 receptor-associated protein 2
• Gene Name: PSMD2
• Related Disease:
  Hepatocellular carcinoma
  Malaria
  Non-insulin dependent diabetes
  Adult lymphoma
  Adult T-cell leukemia/lymphoma
  Alzheimer disease
  Alzheimer disease 3
  B-cell acute lymphoblastic leukaemia
  Breast cancer
  Breast carcinoma
  Cervical Intraepithelial neoplasia
  Endometriosis
  Frontotemporal dementia
  Glioblastoma multiforme
  Inclusion body myopathy with Paget disease of bone and frontotemporal dementia
  Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1
  Lung cancer
  Lung carcinoma
  Lymphoma
  Mantle cell lymphoma
  Pediatric lymphoma
  Pick disease
  Plasma cell myeloma
  Premature aging syndrome
  Squamous cell carcinoma
  Amyotrophic lateral sclerosis
  Cervical carcinoma
  Dementia
  Herpes simplex infection
  Influenza
  Lung adenocarcinoma
  Gastric cancer
  Stomach cancer
  Ankylosing spondylitis
  Bone Paget disease
  Carcinoma
  Cervical cancer
  Cutaneous squamous cell carcinoma
  Enterovirus infection
  Melanoma
  Myopathy
  Nervous system disease
  Spinocerebellar ataxia type 3
• UniProt ID: PSMD2_HUMAN
• PDB ID: 5GJQ ; 5GJR ; 5L4K ; 5LN3 ; 5T0C ; 5T0G ; 5T0H ; 5T0I ; 5T0J ; 5VFP ; 5VFQ ; 5VFR ; 5VFS ; 5VFT ; 5VFU ; 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 ; 7UIH ; 7UJD ; 7W37 ; 7W38 ; 7W39 ; 7W3A ; 7W3B ; 7W3C ; 7W3F ; 7W3G ; 7W3H ; 7W3I ; 7W3J ; 7W3K ; 7W3M ; 8CVT
• Pfam ID: PF01851 ; PF18051 ; PF17781
• Sequence:
  MEEGGRDKAPVQPQQSPAAAPGGTDEKPSGKERRDAGDKDKEQELSEEDKQLQDELEMLV
  ERLGEKDTSLYRPALEELRRQIRSSTTSMTSVPKPLKFLRPHYGKLKEIYENMAPGENKR
  FAADIISVLAMTMSGERECLKYRLVGSQEELASWGHEYVRHLAGEVAKEWQELDDAEKVQ
  REPLLTLVKEIVPYNMAHNAEHEACDLLMEIEQVDMLEKDIDENAYAKVCLYLTSCVNYV
  PEPENSALLRCALGVFRKFSRFPEALRLALMLNDMELVEDIFTSCKDVVVQKQMAFMLGR
  HGVFLELSEDVEEYEDLTEIMSNVQLNSNFLALARELDIMEPKVPDDIYKTHLENNRFGG
  SGSQVDSARMNLASSFVNGFVNAAFGQDKLLTDDGNKWLYKNKDHGMLSAAASLGMILLW
  DVDGGLTQIDKYLYSSEDYIKSGALLACGIVNSGVRNECDPALALLSDYVLHNSNTMRLG
  SIFGLGLAYAGSNREDVLTLLLPVMGDSKSSMEVAGVTALACGMIAVGSCNGDVTSTILQ
  TIMEKSETELKDTYARWLPLGLGLNHLGKGEAIEAILAALEVVSEPFRSFANTLVDVCAY
  AGSGNVLKVQQLLHICSEHFDSKEKEEDKDKKEKKDKDKKEAPADMGAHQGVAVLGIALI
  AMGEEIGAEMALRTFGHLLRYGEPTLRRAVPLALALISVSNPRLNILDTLSKFSHDADPE
  VSYNSIFAMGMVGSGTNNARLAAMLRQLAQYHAKDPNNLFMVRLAQGLTHLGKGTLTLCP
  YHSDRQLMSQVAVAGLLTVLVSFLDVRNIILGKSHYVLYGLVAAMQPRMLVTFDEELRPL
  PVSVRVGQAVDVVGQAGKPKTITGFQTHTTPVLLAHGERAELATEEFLPVTPILEGFVIL
  RKNPNYDL
• 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; Binds to the intracellular domain of tumor necrosis factor type 1 receptor. The binding domain of TRAP1 and TRAP2 resides outside the death domain of TNFR1.
• Tissue Specificity: Found in skeletal muscle, liver, heart, brain, kidney, pancreas, lung and placenta.
• 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)
  Neutrophil degranulation (R-HSA-6798695)
  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

43 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Altered Expression	[1]
Malaria	DISQ9Y50	Definitive	Biomarker	[2]
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Biomarker	[3]
Adult lymphoma	DISK8IZR	Strong	Altered Expression	[4]
Adult T-cell leukemia/lymphoma	DIS882XU	Strong	Biomarker	[5]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[6]
Alzheimer disease 3	DISVT69G	Strong	Altered Expression	[6]
B-cell acute lymphoblastic leukaemia	DISKLOKC	Strong	Biomarker	[7]
Breast cancer	DIS7DPX1	Strong	Biomarker	[8]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[8]
Cervical Intraepithelial neoplasia	DISXP757	Strong	Posttranslational Modification	[9]
Endometriosis	DISX1AG8	Strong	Altered Expression	[10]
Frontotemporal dementia	DISKYHXL	Strong	Genetic Variation	[11]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[12]
Inclusion body myopathy with Paget disease of bone and frontotemporal dementia	DISK4S94	Strong	Genetic Variation	[13]
Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1	DISHQXXA	Strong	Genetic Variation	[14]
Lung cancer	DISCM4YA	Strong	Biomarker	[15]
Lung carcinoma	DISTR26C	Strong	Biomarker	[15]
Lymphoma	DISN6V4S	Strong	Altered Expression	[4]
Mantle cell lymphoma	DISFREOV	Strong	Biomarker	[16]
Pediatric lymphoma	DIS51BK2	Strong	Altered Expression	[4]
Pick disease	DISP6X50	Strong	Genetic Variation	[11]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[17]
Premature aging syndrome	DIS51AGT	Strong	Biomarker	[18]
Squamous cell carcinoma	DISQVIFL	Strong	Posttranslational Modification	[9]
Amyotrophic lateral sclerosis	DISF7HVM	moderate	Genetic Variation	[19]
Cervical carcinoma	DIST4S00	moderate	Biomarker	[20]
Dementia	DISXL1WY	moderate	Biomarker	[21]
Herpes simplex infection	DISL1SAV	moderate	Altered Expression	[22]
Influenza	DIS3PNU3	moderate	Altered Expression	[22]
Lung adenocarcinoma	DISD51WR	moderate	Biomarker	[20]
Gastric cancer	DISXGOUK	Disputed	Altered Expression	[23]
Stomach cancer	DISKIJSX	Disputed	Altered Expression	[23]
Ankylosing spondylitis	DISRC6IR	Limited	Genetic Variation	[24]
Bone Paget disease	DISIPS4V	Limited	Genetic Variation	[25]
Carcinoma	DISH9F1N	Limited	Biomarker	[26]
Cervical cancer	DISFSHPF	Limited	Biomarker	[27]
Cutaneous squamous cell carcinoma	DIS3LXUG	Limited	Altered Expression	[28]
Enterovirus infection	DISH2UDP	Limited	Biomarker	[29]
Melanoma	DIS1RRCY	Limited	Biomarker	[30]
Myopathy	DISOWG27	Limited	Genetic Variation	[11]
Nervous system disease	DISJ7GGT	Limited	Genetic Variation	[31]
Spinocerebellar ataxia type 3	DISQBQID	Limited	Biomarker	[32]

9 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 non-ATPase regulatory subunit 2 (PSMD2).	[33]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of 26S proteasome non-ATPase regulatory subunit 2 (PSMD2).	[34]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of 26S proteasome non-ATPase regulatory subunit 2 (PSMD2).	[35]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 26S proteasome non-ATPase regulatory subunit 2 (PSMD2).	[36]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of 26S proteasome non-ATPase regulatory subunit 2 (PSMD2).	[37]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of 26S proteasome non-ATPase regulatory subunit 2 (PSMD2).	[38]
MG-132	DMKA2YS	Preclinical	MG-132 increases the expression of 26S proteasome non-ATPase regulatory subunit 2 (PSMD2).	[42]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of 26S proteasome non-ATPase regulatory subunit 2 (PSMD2).	[43]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of 26S proteasome non-ATPase regulatory subunit 2 (PSMD2).	[44]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of 26S proteasome non-ATPase regulatory subunit 2 (PSMD2).	[39]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of 26S proteasome non-ATPase regulatory subunit 2 (PSMD2).	[40]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of 26S proteasome non-ATPase regulatory subunit 2 (PSMD2).	[41]

References

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