Details of Drug Off-Target (DOT)

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

• DOT Name: Protein zyg-11 homolog B
• Gene Name: ZYG11B
• Related Disease: Multiple congenital anomalies/dysmorphic syndrome
• UniProt ID: ZY11B_HUMAN
• PDB ID: 7EP0; 7EP1; 7EP2; 7XV7; 7XYV; 7XYW; 7XYX; 7YC2
• Sequence:
  MPEDQAGAAMEEASPYSLLDICLNFLTTHLEKFCSARQDGTLCLQEPGVFPQEVADRLLR
  TMAFHGLLNDGTVGIFRGNQMRLKRACIRKAKISAVAFRKAFCHHKLVELDATGVNADIT
  ITDIISGLGSNKWIQQNLQCLVLNSLTLSLEDPYERCFSRLSGLRALSITNVLFYNEDLA
  EVASLPRLESLDISNTSITDITALLACKDRLKSLTMHHLKCLKMTTTQILDVVRELKHLN
  HLDISDDKQFTSDIALRLLEQKDILPNLVSLDVSGRKHVTDKAVEAFIQQRPSMQFVGLL
  ATDAGYSEFLTGEGHLKVSGEANETQIAEALKRYSERAFFVREALFHLFSLTHVMEKTKP
  EILKLVVTGMRNHPMNLPVQLAASACVFNLTKQDLAAGMPVRLLADVTHLLLKAMEHFPN
  HQQLQKNCLLSLCSDRILQDVPFNRFEAAKLVMQWLCNHEDQNMQRMAVAIISILAAKLS
  TEQTAQLGTELFIVRQLLQIVKQKTNQNSVDTTLKFTLSALWNLTDESPTTCRHFIENQG
  LELFMRVLESFPTESSIQQKVLGLLNNIAEVQELHSELMWKDFIDHISSLLHSVEVEVSY
  FAAGIIAHLISRGEQAWTLSRSQRNSLLDDLHSAILKWPTPECEMVAYRSFNPFFPLLGC
  FTTPGVQLWAVWAMQHVCSKNPSRYCSMLIEEGGLQHLYNIKDHEHTDPHVQQIAVAILD
  SLEKHIVRHGRPPPCKKQPQARLN
• Function: Serves as substrate adapter subunit in the E3 ubiquitin ligase complex ZYG11B-CUL2-Elongin BC. Acts to target substrates bearing N-terminal degrons for proteasomal degradation with the first four residues of substrates being the key recognition elements. Prefers Nt-Gly but also has the capacity to recognize Nt-Ser, -Ala and -Cys. Involved in the clearance of proteolytic fragments generated by caspase cleavage during apoptosis since N-terminal glycine degrons are strongly enriched at caspase cleavage sites. Also important in the quality control of protein N-myristoylation in which N-terminal glycine degrons are conditionally exposed after a failure of N-myristoylation. In addition, plays a role in the amplification of cGAS to enhance innate immune response. Mechanistically, strengthens the processes of cGAS binding with dsDNA and assembling oligomers and also accelerates and stabilizes cGAS-DNA condensation, thereby enhancing production of antiviral IFNs and inflammatory cytokines.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Multiple congenital anomalies/dysmorphic syndrome	DIS0LF2K	Limited	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Protein zyg-11 homolog B.	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein zyg-11 homolog B.	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein zyg-11 homolog B.	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein zyg-11 homolog B.	[5]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Protein zyg-11 homolog B.	[6]
Marinol	DM70IK5	Approved	Marinol increases the expression of Protein zyg-11 homolog B.	[7]
Tanespimycin	DMNLQHK	Phase 2	Tanespimycin increases the expression of Protein zyg-11 homolog B.	[8]
NVP-AUY922	DMTYXQF	Phase 2	NVP-AUY922 increases the expression of Protein zyg-11 homolog B.	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Protein zyg-11 homolog B.	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Protein zyg-11 homolog B.	[11]

1 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 decreases the methylation of Protein zyg-11 homolog B.	[9]

References

• [1] 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.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [4] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [5] 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.
• [6] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [7] Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. Mol Hum Reprod. 2006 May;12(5):321-33. doi: 10.1093/molehr/gal036. Epub 2006 Apr 5.
• [8] Impact of Heat Shock Protein 90 Inhibition on the Proteomic Profile of Lung Adenocarcinoma as Measured by Two-Dimensional Electrophoresis Coupled with Mass Spectrometry. Cells. 2019 Jul 31;8(8):806. doi: 10.3390/cells8080806.
• [9] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [10] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [11] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.