Details of Drug Off-Target (DOT)

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

• DOT Name: ER membrane protein complex subunit 4 (EMC4)
• Synonyms: Cell proliferation-inducing gene 17 protein; Transmembrane protein 85
• Gene Name: EMC4
• UniProt ID: EMC4_HUMAN
• PDB ID: 6Z3W; 7ADO; 7ADP; 8EOI; 8S9S
• Pfam ID: PF06417
• Sequence:
  MTAQGGLVANRGRRFKWAIELSGPGGGSRGRSDRGSGQGDSLYPVGYLDKQVPDTSVQET
  DRILVEKRCWDIALGPLKQIPMNLFIMYMAGNTISIFPTMMVCMMAWRPIQALMAISATF
  KMLESSSQKFLQGLVYLIGNLMGLALAVYKCQSMGLLPTHASDWLAFIEPPERMEFSGGG
  LLL
• Function: Part of the endoplasmic reticulum membrane protein complex (EMC) that enables the energy-independent insertion into endoplasmic reticulum membranes of newly synthesized membrane proteins. Preferentially accommodates proteins with transmembrane domains that are weakly hydrophobic or contain destabilizing features such as charged and aromatic residues. Involved in the cotranslational insertion of multi-pass membrane proteins in which stop-transfer membrane-anchor sequences become ER membrane spanning helices. It is also required for the post-translational insertion of tail-anchored/TA proteins in endoplasmic reticulum membranes. By mediating the proper cotranslational insertion of N-terminal transmembrane domains in an N-exo topology, with translocated N-terminus in the lumen of the ER, controls the topology of multi-pass membrane proteins like the G protein-coupled receptors. By regulating the insertion of various proteins in membranes, it is indirectly involved in many cellular processes (Probable).
• Tissue Specificity: Isoform 1 is expressed in brain and heart. Isoform 2 is expressed in heart.

Molecular Interaction Atlas (MIA) of This DOT

5 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 ER membrane protein complex subunit 4 (EMC4).	[1]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of ER membrane protein complex subunit 4 (EMC4).	[2]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ER membrane protein complex subunit 4 (EMC4).	[3]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of ER membrane protein complex subunit 4 (EMC4).	[5]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of ER membrane protein complex subunit 4 (EMC4).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of ER membrane protein complex subunit 4 (EMC4).	[4]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] 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.
• [3] 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.
• [4] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [5] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [6] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.