Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWIX1JU)

• DOT Name: Transitional endoplasmic reticulum ATPase
• Synonyms: TER ATPase; EC 3.6.4.6; 15S Mg(2+)-ATPase p97 subunit; Valosin-containing protein; VCP
• Gene Name: VCP
• Related Disease:
  Inclusion body myopathy with Paget disease of bone and frontotemporal dementia
  Charcot-Marie-Tooth disease type 2Y
  Frontotemporal dementia and/or amyotrophic lateral sclerosis 6
  Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1
  Adult-onset distal myopathy due to VCP mutation
  Amyotrophic lateral sclerosis
  Frontotemporal dementia with motor neuron disease
  Spastic paraplegia-Paget disease of bone syndrome
• UniProt ID: TERA_HUMAN
• PDB ID: 3EBB ; 3HU1 ; 3HU2 ; 3HU3 ; 3QC8 ; 3QQ7 ; 3QQ8 ; 3QWZ ; 3TIW ; 4KDI ; 4KDL ; 4KLN ; 4KO8 ; 4KOD ; 4P0A ; 5B6C ; 5C18 ; 5C19 ; 5C1A ; 5C1B ; 5DYG ; 5DYI ; 5EPP ; 5FTJ ; 5FTK ; 5FTL ; 5FTM ; 5FTN ; 5GLF ; 5IFS ; 5IFW ; 5KIW ; 5KIY ; 5X4L ; 6G2V ; 6G2W ; 6G2X ; 6G2Y ; 6G2Z ; 6G30 ; 6HD0 ; 6MCK ; 7BP8 ; 7BP9 ; 7BPA ; 7BPB ; 7JY5 ; 7K56 ; 7K57 ; 7K59 ; 7L5W ; 7L5X ; 7LMY ; 7LMZ ; 7LN0 ; 7LN1 ; 7LN2 ; 7LN3 ; 7LN4 ; 7LN5 ; 7LN6 ; 7MDM ; 7MDO ; 7MHS ; 7OAT ; 7PUX ; 7R7S ; 7R7T ; 7R7U ; 7RL6 ; 7RL7 ; 7RL9 ; 7RLA ; 7RLB ; 7RLC ; 7RLD ; 7RLF ; 7RLG ; 7RLH ; 7RLI ; 7RLJ ; 7VCS ; 7VCT ; 7VCU ; 7VCV ; 7VCX ; 7Y4W ; 7Y53 ; 7Y59 ; 8B5R ; 8FCL ; 8FCM ; 8FCN ; 8FCO ; 8FCP ; 8FCQ ; 8FCR ; 8FCT ; 8HL7
• EC Number: 3.6.4.6
• Pfam ID: PF00004 ; PF17862 ; PF02933 ; PF02359
• Sequence:
  MASGADSKGDDLSTAILKQKNRPNRLIVDEAINEDNSVVSLSQPKMDELQLFRGDTVLLK
  GKKRREAVCIVLSDDTCSDEKIRMNRVVRNNLRVRLGDVISIQPCPDVKYGKRIHVLPID
  DTVEGITGNLFEVYLKPYFLEAYRPIRKGDIFLVRGGMRAVEFKVVETDPSPYCIVAPDT
  VIHCEGEPIKREDEEESLNEVGYDDIGGCRKQLAQIKEMVELPLRHPALFKAIGVKPPRG
  ILLYGPPGTGKTLIARAVANETGAFFFLINGPEIMSKLAGESESNLRKAFEEAEKNAPAI
  IFIDELDAIAPKREKTHGEVERRIVSQLLTLMDGLKQRAHVIVMAATNRPNSIDPALRRF
  GRFDREVDIGIPDATGRLEILQIHTKNMKLADDVDLEQVANETHGHVGADLAALCSEAAL
  QAIRKKMDLIDLEDETIDAEVMNSLAVTMDDFRWALSQSNPSALRETVVEVPQVTWEDIG
  GLEDVKRELQELVQYPVEHPDKFLKFGMTPSKGVLFYGPPGCGKTLLAKAIANECQANFI
  SIKGPELLTMWFGESEANVREIFDKARQAAPCVLFFDELDSIAKARGGNIGDGGGAADRV
  INQILTEMDGMSTKKNVFIIGATNRPDIIDPAILRPGRLDQLIYIPLPDEKSRVAILKAN
  LRKSPVAKDVDLEFLAKMTNGFSGADLTEICQRACKLAIRESIESEIRRERERQTNPSAM
  EVEEDDPVPEIRRDHFEEAMRFARRSVSDNDIRKYEMFAQTLQQSRGFGSFRFPSGNQGG
  AGPSQGSGGGTGGSVYTEDNDDDLYG
• Function: Necessary for the fragmentation of Golgi stacks during mitosis and for their reassembly after mitosis. Involved in the formation of the transitional endoplasmic reticulum (tER). The transfer of membranes from the endoplasmic reticulum to the Golgi apparatus occurs via 50-70 nm transition vesicles which derive from part-rough, part-smooth transitional elements of the endoplasmic reticulum (tER). Vesicle budding from the tER is an ATP-dependent process. The ternary complex containing UFD1, VCP and NPLOC4 binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome. The NPLOC4-UFD1-VCP complex regulates spindle disassembly at the end of mitosis and is necessary for the formation of a closed nuclear envelope. Regulates E3 ubiquitin-protein ligase activity of RNF19A. Component of the VCP/p97-AMFR/gp78 complex that participates in the final step of the sterol-mediated ubiquitination and endoplasmic reticulum-associated degradation (ERAD) of HMGCR. Mediates the endoplasmic reticulum-associated degradation of CHRNA3 in cortical neurons as part of the STUB1-VCP-UBXN2A complex. Involved in endoplasmic reticulum stress-induced pre-emptive quality control, a mechanism that selectively attenuates the translocation of newly synthesized proteins into the endoplasmic reticulum and reroutes them to the cytosol for proteasomal degradation. Involved in clearance process by mediating G3BP1 extraction from stress granules. Also involved in DNA damage response: recruited to double-strand breaks (DSBs) sites in a RNF8- and RNF168-dependent manner and promotes the recruitment of TP53BP1 at DNA damage sites. Recruited to stalled replication forks by SPRTN: may act by mediating extraction of DNA polymerase eta (POLH) to prevent excessive translesion DNA synthesis and limit the incidence of mutations induced by DNA damage. Together with SPRTN metalloprotease, involved in the repair of covalent DNA-protein cross-links (DPCs) during DNA synthesis. Involved in interstrand cross-link repair in response to replication stress by mediating unloading of the ubiquitinated CMG helicase complex. Mediates extraction of PARP1 trapped to chromatin: recognizes and binds ubiquitinated PARP1 and promotes its removal. Required for cytoplasmic retrotranslocation of stressed/damaged mitochondrial outer-membrane proteins and their subsequent proteasomal degradation. Essential for the maturation of ubiquitin-containing autophagosomes and the clearance of ubiquitinated protein by autophagy. Acts as a negative regulator of type I interferon production by interacting with RIGI: interaction takes place when RIGI is ubiquitinated via 'Lys-63'-linked ubiquitin on its CARD domains, leading to recruit RNF125 and promote ubiquitination and degradation of RIGI. May play a role in the ubiquitin-dependent sorting of membrane proteins to lysosomes where they undergo degradation. May more particularly play a role in caveolins sorting in cells. By controlling the steady-state expression of the IGF1R receptor, indirectly regulates the insulin-like growth factor receptor signaling pathway.
• KEGG Pathway:
  Mitophagy - animal (hsa04137)
  Protein processing in endoplasmic reticulum (hsa04141)
  Amyotrophic lateral sclerosis (hsa05014)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Legionellosis (hsa05134)
• Reactome Pathway:
  HSF1 activation (R-HSA-3371511)
  ABC-family proteins mediated transport (R-HSA-382556)
  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)
  Defective CFTR causes cystic fibrosis (R-HSA-5678895)
  Josephin domain DUBs (R-HSA-5689877)
  Ovarian tumor domain proteases (R-HSA-5689896)
  Neutrophil degranulation (R-HSA-6798695)
  E3 ubiquitin ligases ubiquitinate target proteins (R-HSA-8866654)
  Protein methylation (R-HSA-8876725)
  Neddylation (R-HSA-8951664)
  RHOH GTPase cycle (R-HSA-9013407)
  Aggrephagy (R-HSA-9646399)
  Attachment and Entry (R-HSA-9678110)
  Attachment and Entry (R-HSA-9694614)
  KEAP1-NFE2L2 pathway (R-HSA-9755511)
  Translesion Synthesis by POLH (R-HSA-110320)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Inclusion body myopathy with Paget disease of bone and frontotemporal dementia	DISK4S94	Definitive	Autosomal dominant	[1]
Charcot-Marie-Tooth disease type 2Y	DISBXPPB	Strong	Autosomal dominant	[2]
Frontotemporal dementia and/or amyotrophic lateral sclerosis 6	DISNWZJK	Strong	Autosomal dominant	[3]
Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1	DISHQXXA	Strong	Autosomal dominant	[4]
Adult-onset distal myopathy due to VCP mutation	DIS4PJCD	Supportive	Autosomal dominant	[5]
Amyotrophic lateral sclerosis	DISF7HVM	Supportive	Autosomal dominant	[6]
Frontotemporal dementia with motor neuron disease	DISPZM6A	Supportive	Autosomal dominant	[7]
Spastic paraplegia-Paget disease of bone syndrome	DISUEXRV	Supportive	Autosomal dominant	[8]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
PEITC	DMOMN31	Phase 2	Transitional endoplasmic reticulum ATPase affects the binding of PEITC.	[34]
Sulforaphane	DMQY3L0	Investigative	Transitional endoplasmic reticulum ATPase affects the binding of Sulforaphane.	[34]
NMS-873	DMYKZ6U	Investigative	Transitional endoplasmic reticulum ATPase decreases the response to substance of NMS-873.	[35]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Transitional endoplasmic reticulum ATPase.	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Transitional endoplasmic reticulum ATPase.	[10]
Arsenic	DMTL2Y1	Approved	Arsenic increases the ubiquitination of Transitional endoplasmic reticulum ATPase.	[14]
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of Transitional endoplasmic reticulum ATPase.	[15]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Transitional endoplasmic reticulum ATPase.	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Transitional endoplasmic reticulum ATPase.	[28]

18 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Transitional endoplasmic reticulum ATPase.	[11]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Transitional endoplasmic reticulum ATPase.	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Transitional endoplasmic reticulum ATPase.	[13]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Transitional endoplasmic reticulum ATPase.	[16]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Transitional endoplasmic reticulum ATPase.	[17]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Transitional endoplasmic reticulum ATPase.	[18]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Transitional endoplasmic reticulum ATPase.	[19]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Transitional endoplasmic reticulum ATPase.	[20]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Transitional endoplasmic reticulum ATPase.	[22]
CB-5083	DM12GN7	Phase 1	CB-5083 decreases the activity of Transitional endoplasmic reticulum ATPase.	[24]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Transitional endoplasmic reticulum ATPase.	[25]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the expression of Transitional endoplasmic reticulum ATPase.	[26]
MG-132	DMKA2YS	Preclinical	MG-132 increases the expression of Transitional endoplasmic reticulum ATPase.	[27]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Transitional endoplasmic reticulum ATPase.	[29]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Transitional endoplasmic reticulum ATPase.	[30]
Okadaic acid	DM47CO1	Investigative	Okadaic acid decreases the expression of Transitional endoplasmic reticulum ATPase.	[31]
Taurine	DMVW7N3	Investigative	Taurine decreases the expression of Transitional endoplasmic reticulum ATPase.	[32]
L-Serine	DM6WPIS	Investigative	L-Serine decreases the expression of Transitional endoplasmic reticulum ATPase.	[33]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Transitional endoplasmic reticulum ATPase.	[21]

References

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