Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD3YPVL)

• DOT Name: DNA mismatch repair protein Msh3 (MSH3)
• Synonyms: hMSH3; Divergent upstream protein; DUP; Mismatch repair protein 1; MRP1
• Gene Name: MSH3
• Related Disease:
  Matthew-Wood syndrome
  Adenocarcinoma
  Adult T-cell leukemia/lymphoma
  Bladder cancer
  Bone osteosarcoma
  Carcinoma
  Colon carcinoma
  Epithelial ovarian cancer
  Esophageal cancer
  Familial adenomatous polyposis
  Familial adenomatous polyposis 4
  Gastric cancer
  Glioblastoma multiforme
  Glioma
  Hepatocellular carcinoma
  Huntington disease
  Lung adenocarcinoma
  Metastatic malignant neoplasm
  Neuroblastoma
  Non-insulin dependent diabetes
  Osteosarcoma
  Ovarian cancer
  Ovarian neoplasm
  Plasma cell myeloma
  Squamous cell carcinoma
  T-cell leukaemia
  Urinary bladder cancer
  Urinary bladder neoplasm
  Acute leukaemia
  Acute monocytic leukemia
  Adult glioblastoma
  Childhood acute lymphoblastic leukemia
  Cystic fibrosis
  Melanoma
  Prostate cancer
  Obsolete MSH3-related attenuated familial adenomatous polyposis
  Lung cancer
  Lung carcinoma
  Astrocytoma
  B-cell neoplasm
  Colon cancer
  Endometrial carcinoma
  Lynch syndrome
  Lynch syndrome 1
  Lynch syndrome 2
  Prostate carcinoma
  Prostate neoplasm
  Small-cell lung cancer
  Stomach cancer
• UniProt ID: MSH3_HUMAN
• PDB ID: 3THW; 3THX; 3THY; 3THZ; 8OLX; 8OM5; 8OM9; 8OMA; 8OMO; 8OMQ
• Pfam ID: PF01624 ; PF05188 ; PF05192 ; PF00488
• Sequence:
  MSRRKPASGGLAASSSAPARQAVLSRFFQSTGSLKSTSSSTGAADQVDPGAAAAAAAAAA
  AAPPAPPAPAFPPQLPPHIATEIDRRKKRPLENDGPVKKKVKKVQQKEGGSDLGMSGNSE
  PKKCLRTRNVSKSLEKLKEFCCDSALPQSRVQTESLQERFAVLPKCTDFDDISLLHAKNA
  VSSEDSKRQINQKDTTLFDLSQFGSSNTSHENLQKTASKSANKRSKSIYTPLELQYIEMK
  QQHKDAVLCVECGYKYRFFGEDAEIAARELNIYCHLDHNFMTASIPTHRLFVHVRRLVAK
  GYKVGVVKQTETAALKAIGDNRSSLFSRKLTALYTKSTLIGEDVNPLIKLDDAVNVDEIM
  TDTSTSYLLCISENKENVRDKKKGNIFIGIVGVQPATGEVVFDSFQDSASRSELETRMSS
  LQPVELLLPSALSEQTEALIHRATSVSVQDDRIRVERMDNIYFEYSHAFQAVTEFYAKDT
  VDIKGSQIISGIVNLEKPVICSLAAIIKYLKEFNLEKMLSKPENFKQLSSKMEFMTINGT
  TLRNLEILQNQTDMKTKGSLLWVLDHTKTSFGRRKLKKWVTQPLLKLREINARLDAVSEV
  LHSESSVFGQIENHLRKLPDIERGLCSIYHKKCSTQEFFLIVKTLYHLKSEFQAIIPAVN
  SHIQSDLLRTVILEIPELLSPVEHYLKILNEQAAKVGDKTELFKDLSDFPLIKKRKDEIQ
  GVIDEIRMHLQEIRKILKNPSAQYVTVSGQEFMIEIKNSAVSCIPTDWVKVGSTKAVSRF
  HSPFIVENYRHLNQLREQLVLDCSAEWLDFLEKFSEHYHSLCKAVHHLATVDCIFSLAKV
  AKQGDYCRPTVQEERKIVIKNGRHPVIDVLLGEQDQYVPNNTDLSEDSERVMIITGPNMG
  GKSSYIKQVALITIMAQIGSYVPAEEATIGIVDGIFTRMGAADNIYKGQSTFMEELTDTA
  EIIRKATSQSLVILDELGRGTSTHDGIAIAYATLEYFIRDVKSLTLFVTHYPPVCELEKN
  YSHQVGNYHMGFLVSEDESKLDPGAAEQVPDFVTFLYQITRGIAARSYGLNVAKLADVPG
  EILKKAAHKSKELEGLINTKRKRLKYFAKLWTMHNAQDLQKWTEEFNMEETQTSLLH
• Function: Component of the post-replicative DNA mismatch repair system (MMR). Heterodimerizes with MSH2 to form MutS beta which binds to DNA mismatches thereby initiating DNA repair. When bound, the MutS beta heterodimer bends the DNA helix and shields approximately 20 base pairs. MutS beta recognizes large insertion-deletion loops (IDL) up to 13 nucleotides long. After mismatch binding, forms a ternary complex with the MutL alpha heterodimer, which is thought to be responsible for directing the downstream MMR events, including strand discrimination, excision, and resynthesis.
• KEGG Pathway:
  Platinum drug resistance (hsa01524)
  Mismatch repair (hsa03430)
  Pathways in cancer (hsa05200)
  Colorectal cancer (hsa05210)
• Reactome Pathway:
  Defective Mismatch Repair Associated With MSH3 (R-HSA-5632927)
  Defective Mismatch Repair Associated With MSH2 (R-HSA-5632928)
  Mismatch repair (MMR) directed by MSH2 (R-HSA-5358606)

Molecular Interaction Atlas (MIA) of This DOT

49 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Matthew-Wood syndrome	DISA7HR7	Definitive	Altered Expression	[1]
Adenocarcinoma	DIS3IHTY	Strong	Genetic Variation	[2]
Adult T-cell leukemia/lymphoma	DIS882XU	Strong	Biomarker	[3]
Bladder cancer	DISUHNM0	Strong	Biomarker	[4]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[5]
Carcinoma	DISH9F1N	Strong	Biomarker	[6]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[7]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[8]
Esophageal cancer	DISGB2VN	Strong	Genetic Variation	[9]
Familial adenomatous polyposis	DISW53RE	Strong	Genetic Variation	[10]
Familial adenomatous polyposis 4	DIS2FW8J	Strong	Autosomal recessive	[11]
Gastric cancer	DISXGOUK	Strong	Biomarker	[12]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[13]
Glioma	DIS5RPEH	Strong	Altered Expression	[14]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[15]
Huntington disease	DISQPLA4	Strong	Genetic Variation	[16]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[17]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[18]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[19]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[20]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[5]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[8]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[8]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[21]
Squamous cell carcinoma	DISQVIFL	Strong	Genetic Variation	[2]
T-cell leukaemia	DISJ6YIF	Strong	Biomarker	[3]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[4]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[4]
Acute leukaemia	DISDQFDI	moderate	Biomarker	[22]
Acute monocytic leukemia	DIS28NEL	moderate	Altered Expression	[23]
Adult glioblastoma	DISVP4LU	moderate	Biomarker	[13]
Childhood acute lymphoblastic leukemia	DISJ5D6U	moderate	Biomarker	[24]
Cystic fibrosis	DIS2OK1Q	moderate	Biomarker	[25]
Melanoma	DIS1RRCY	moderate	Altered Expression	[26]
Prostate cancer	DISF190Y	moderate	Genetic Variation	[27]
Obsolete MSH3-related attenuated familial adenomatous polyposis	DISOE3NP	Supportive	Autosomal recessive	[28]
Lung cancer	DISCM4YA	Disputed	Altered Expression	[29]
Lung carcinoma	DISTR26C	Disputed	Altered Expression	[29]
Astrocytoma	DISL3V18	Limited	Biomarker	[30]
B-cell neoplasm	DISVY326	Limited	Altered Expression	[31]
Colon cancer	DISVC52G	Limited	Altered Expression	[7]
Endometrial carcinoma	DISXR5CY	Limited	Biomarker	[32]
Lynch syndrome	DIS3IW5F	Limited	Autosomal dominant	[33]
Lynch syndrome 1	DISSABLZ	Limited	Biomarker	[28]
Lynch syndrome 2	DISRLYU1	Limited	Biomarker	[28]
Prostate carcinoma	DISMJPLE	Limited	Genetic Variation	[27]
Prostate neoplasm	DISHDKGQ	Limited	Biomarker	[34]
Small-cell lung cancer	DISK3LZD	Limited	Biomarker	[35]
Stomach cancer	DISKIJSX	Limited	Biomarker	[12]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	DNA mismatch repair protein Msh3 (MSH3) decreases the response to substance of Cisplatin.	[46]
Olaparib	DM8QB1D	Approved	DNA mismatch repair protein Msh3 (MSH3) decreases the response to substance of Olaparib.	[46]

1 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 DNA mismatch repair protein Msh3 (MSH3).	[36]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of DNA mismatch repair protein Msh3 (MSH3).	[37]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DNA mismatch repair protein Msh3 (MSH3).	[38]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of DNA mismatch repair protein Msh3 (MSH3).	[39]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of DNA mismatch repair protein Msh3 (MSH3).	[40]
Vandetanib	DMRICNP	Approved	Vandetanib decreases the expression of DNA mismatch repair protein Msh3 (MSH3).	[41]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of DNA mismatch repair protein Msh3 (MSH3).	[42]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of DNA mismatch repair protein Msh3 (MSH3).	[43]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of DNA mismatch repair protein Msh3 (MSH3).	[44]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of DNA mismatch repair protein Msh3 (MSH3).	[45]

References

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