Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUIN61P)

• DOT Name: PAT complex subunit CCDC47 (CCDC47)
• Synonyms: Calumin; Coiled-coil domain-containing protein 47
• Gene Name: CCDC47
• Related Disease:
  Hypertrophic cardiomyopathy
  Intellectual disability
  Isolated familial wooly hair disorder
  Liver disease
  Trichohepatoneurodevelopmental syndrome
• UniProt ID: CCD47_HUMAN
• PDB ID: 6W6L
• Pfam ID: PF07946
• Sequence:
  MKAFHTFCVVLLVFGSVSEAKFDDFEDEEDIVEYDDNDFAEFEDVMEDSVTESPQRVIIT
  EDDEDETTVELEGQDENQEGDFEDADTQEGDTESEPYDDEEFEGYEDKPDTSSSKNKDPI
  TIVDVPAHLQNSWESYYLEILMVTGLLAYIMNYIIGKNKNSRLAQAWFNTHRELLESNFT
  LVGDDGTNKEATSTGKLNQENEHIYNLWCSGRVCCEGMLIQLRFLKRQDLLNVLARMMRP
  VSDQVQIKVTMNDEDMDTYVFAVGTRKALVRLQKEMQDLSEFCSDKPKSGAKYGLPDSLA
  ILSEMGEVTDGMMDTKMVHFLTHYADKIESVHFSDQFSGPKIMQEEGQPLKLPDTKRTLL
  FTFNVPGSGNTYPKDMEALLPLMNMVIYSIDKAKKFRLNREGKQKADKNRARVEENFLKL
  THVQRQEAAQSRREEKKRAEKERIMNEEDPEKQRRLEEAALRREQKKLEKKQMKMKQIKV
  KAM
• Function: Component of the multi-pass translocon (MPT) complex that mediates insertion of multi-pass membrane proteins into the lipid bilayer of membranes. The MPT complex takes over after the SEC61 complex: following membrane insertion of the first few transmembrane segments of proteins by the SEC61 complex, the MPT complex occludes the lateral gate of the SEC61 complex to promote insertion of subsequent transmembrane regions. Within the MPT complex, the PAT subcomplex sequesters any highly polar regions in the transmembrane domains away from the non-polar membrane environment until they can be buried in the interior of the fully assembled protein. Within the PAT subcomplex, CCDC47 occludes the lateral gate of the SEC61 complex. Involved in the regulation of calcium ion homeostasis in the ER. Required for proper protein degradation via the ERAD (ER-associated degradation) pathway. Has an essential role in the maintenance of ER organization during embryogenesis.

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypertrophic cardiomyopathy	DISQG2AI	Strong	Biomarker	[1]
Intellectual disability	DISMBNXP	Strong	Biomarker	[2]
Isolated familial wooly hair disorder	DISTWYN7	Strong	Biomarker	[2]
Liver disease	DIS2OMMF	Strong	Biomarker	[2]
Trichohepatoneurodevelopmental syndrome	DISYU31H	Strong	Autosomal recessive	[2]

7 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 PAT complex subunit CCDC47 (CCDC47).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of PAT complex subunit CCDC47 (CCDC47).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of PAT complex subunit CCDC47 (CCDC47).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of PAT complex subunit CCDC47 (CCDC47).	[7]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of PAT complex subunit CCDC47 (CCDC47).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of PAT complex subunit CCDC47 (CCDC47).	[9]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of PAT complex subunit CCDC47 (CCDC47).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of PAT complex subunit CCDC47 (CCDC47).	[6]

References

• [1] Dysregulation of the calcium handling protein, CCDC47, is associated with diabetic cardiomyopathy.Cell Biosci. 2018 Aug 17;8:45. doi: 10.1186/s13578-018-0244-0. eCollection 2018.
• [2] Bi-allelic CCDC47 Variants Cause a Disorder Characterized by Woolly Hair, Liver Dysfunction, Dysmorphic Features, and Global Developmental Delay. Am J Hum Genet. 2018 Nov 1;103(5):794-807. doi: 10.1016/j.ajhg.2018.09.014. Epub 2018 Oct 25.
• [3] Antiepileptic drugs are endocrine disruptors for the human fetal testis ex vivo. Toxicol Sci. 2023 Sep 28;195(2):169-183. doi: 10.1093/toxsci/kfad076.
• [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] 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.
• [6] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [7] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [8] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [9] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [10] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.