mutLBSgeneDB

mutLBSgeneDB
mutated Ligand Binding Site gene DataBase

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	Gene Summary
	Ligand Binding Site Mutation Information
	Protein Structure Related Information
	Gene Expression and Gene-Gene Network
	Phenotype Information
	Pharmacological Information
	Conservation Information for LBS

Gene summary for CYP2C9

Gene summary

Basic gene Info.	Gene symbol	CYP2C9
	Gene name	cytochrome P450, family 2, subfamily C, polypeptide 9
	Synonyms	CPC9\|CYP2C\|CYP2C10\|CYPIIC9\|P450IIC9
	Cytomap	UCSC genome browser: 10q24
	Type of gene	protein-coding
	RefGenes	NM_000771.3,
	Description	cytochrome P-450 S-mephenytoin 4-hydroxylasecytochrome P-450MPcytochrome P450 2C9cytochrome P450 PB-1flavoprotein-linked monooxygenasemicrosomal monooxygenasexenobiotic monooxygenase
	Modification date	20141211
dbXrefs	MIM : 601130
	HGNC : HGNC
	Ensembl : ENSG00000138109
	HPRD : 03084
	Vega : OTTHUMG00000018805
Protein	UniProt: P11712 go to UniProt's Cross Reference DB Table
Expression	CleanEX: HS_CYP2C9
	BioGPS: 1559
Pathway	NCI Pathway Interaction Database: CYP2C9
	KEGG: CYP2C9
	REACTOME: CYP2C9
	Pathway Commons: CYP2C9
Context	iHOP: CYP2C9
	ligand binding site mutation search in PubMed: CYP2C9
	UCL Cancer Institute: CYP2C9
Assigned class in mutLBSgeneDB	A: This gene has a literature evidence and it belongs to targetable_mutLBSgenes.
References showing study about ligand binding site mutation for CYP2C9.	1. "Haining RL, Jones JP, Henne KR, Fisher MB, Koop DR, Trager WF, Rettie AE. Enzymatic determinants of the substrate specificity of CYP2C9: role of B'-C loop residues in providing the pi-stacking anchor site for warfarin binding. Biochemistry. 1999 Mar 16;38(11):3285-92. PubMed PMID: 10079071. " 10079071 2. "Dickmann LJ, Locuson CW, Jones JP, Rettie AE. Differential roles of Arg97, Asp293, and Arg108 in enzyme stability and substrate specificity of CYP2C9. Mol Pharmacol. 2004 Apr;65(4):842-50. PubMed PMID: 15044613. " 15044613

Gene ontology having evidence of Inferred from Direct Assay (IDA) from Entrez

GO ID	GO Term	PubMed ID
GO:0016098	monoterpenoid metabolic process	16401082
GO:0017144	drug metabolic process	19219744
GO:0019627	urea metabolic process	19029318
GO:0032787	monocarboxylic acid metabolic process	19651758
GO:0042738	exogenous drug catabolic process	18619574
GO:0043603	cellular amide metabolic process	19651758
GO:0055114	oxidation-reduction process	16401082
GO:0070989	oxidative demethylation	18619574

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Ligand binding site mutations for CYP2C9

Cancer type specific mutLBS sorted by frequency

LBS	AAchange of nsSNV	Cancer type	# samples
E444	E444G	COAD	2
S429,R433	G431E	SKCM	2
L233	N231K	COAD	1
R433	R433W	COAD	1
E444	E444K	COAD	1
N107	A106V	KIRC	1
L102,F100	P101Q	LUAD	1
A103	A103V	LUAD	1
L391	I389T	LUSC	1
E444	E444D	OV	1
R108	G109R	SKCM	1
L362,T364	P363S	SKCM	1
R124,W120	E122K	SKCM	1
L391	S390F	SKCM	1

cf) Cancer type abbreviation. BLCA: Bladder urothelial carcinoma, BRCA: Breast invasive carcinoma, CESC: Cervical squamous cell carcinoma and endocervical adenocarcinoma, COAD: Colon adenocarcinoma, GBM: Glioblastoma multiforme, LGG: Brain lower grade glioma, HNSC: Head and neck squamous cell carcinoma, KICH: Kidney chromophobe, KIRC: Kidney renal clear cell carcinoma, KIRP: Kidney renal papillary cell carcinoma, LAML: Acute myeloid leukemia, LUAD: Lung adenocarcinoma, LUSC: Lung squamous cell carcinoma, OV: Ovarian serous cystadenocarcinoma, PAAD: Pancreatic adenocarcinoma, PRAD: Prostate adenocarcinoma, SKCM: Skin cutaneous melanoma, STAD: Stomach adenocarcinoma, THCA: Thyroid carcinoma, UCEC: Uterine corpus endometrial carcinoma.

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Protein structure related information for CYP2C9

Relative protein structure stability change (ΔΔE) using Mupro 1.1
Mupro score denotes assessment of the effect of mutations on thermodynamic stability.
(ΔΔE<0: mutation decreases stability, ΔΔE>0: mutation increases stability)

: nsSNV at non-LBS

: nsSNV at LBS

nsSNVs sorted by the relative stability change of protein structure by each mutation
Blue: mutations of positive stability change. and red : the most recurrent mutation for this gene.

LBS	AAchange of nsSNV	Relative stability change
N107	A106V	0.071331411
A103	A103V	0.031067281
L391	I389T	-1.2443179
F100	P101Q	-1.1103241
L102	P101Q	-1.1103241
S429	G431E	-0.87435855
R433	G431E	-0.87435855
W120	E122K	-0.80202708
R124	E122K	-0.80202708
L391	S390F	-0.78152168
L362	P363S	-0.6773486
T364	P363S	-0.6773486
E444	E444G	-0.67260317
R108	G109R	-0.65122539
R433	R433W	-0.56910267
E444	E444D	-0.34949731
E444	E444K	-0.31850736
L233	N231K	-0.093827882

(MuPro1.1: Jianlin Cheng et al., Prediction of Protein Stability Changes for Single-Site Mutations Using Support Vector Machines, PROTEINS: Structure, Function, and Bioinformatics. 2006, 62:1125-1132)

Structure image for CYP2C9 from PDB

PDB ID	PDB title	PDB structure
1OG2	STRUCTURE OF HUMAN CYTOCHROME P450 CYP2C9

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Differential gene expression and gene-gene network for CYP2C9

Differential gene expression between mutated and non-mutated LBS samples in all 16 major cancer types

Differential co-expressed gene network based on protein-protein interaction data (CePIN)

* Left PPI network was created from samples with mutations in the LBS of CYP2C9 and the right PPI network was created from samples without mutations in the LBS of CYP2C9. Only genes with p-value < 0.05 are shown.
Red circle: input gene. Orange circle: LBSgene. Blue circle: other gene.

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Phenotype information for CYP2C9

Gene level disease information (DisGeNet)

Disease ID	Disease name	# PubMed	Association type
umls:C0019080	Hemorrhage	13	Biomarker, GeneticVariation
umls:C0860207	Drug-Induced Liver Injury	5	Biomarker, GeneticVariation
umls:C0013182	Drug Hypersensitivity	4	Biomarker, GeneticVariation
umls:C0750384	Coumarin Resistance	2	Biomarker, GeneticVariation
umls:C3658338	Drug-Related Side Effects and Adverse Reactions	2	Biomarker
umls:C0030922	Peptic Ulcer Hemorrhage	1	Biomarker, GeneticVariation
umls:C0006118	Brain Neoplasms	1	Biomarker
umls:C2609414	Acute Kidney Injury	1	Biomarker
umls:C0878544	Cardiomyopathies	1	Biomarker
umls:C0027707	Nephritis, Interstitial	1	Biomarker
umls:C0027765	Nervous System Diseases	1	Biomarker

Mutation level pathogenic information (ClinVar annotation)

Allele ID

AA change

Clinical significance

Origin

Phenotype IDs

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Pharmacological information for CYP2C9

Gene expression profile of anticancer drug treated cell-lines (CCLE)
Heatmap showing the correlation between gene expression and drug response across all the cell-lines. We chose the top 20 among 138 drugs.We used Pearson's correlation coefficient.

Gene-centered drug-gene interaction network

Drug information targeting mutLBSgene (Approved drugs only)

Drug status	DrugBank ID	Name	Type	Drug structure
Experimental	DB02507	4-Hydroxy-3-[(1s)-3-Oxo-1-Phenylbutyl]-2h-Chromen-2-One	Small molecule
Experimental	DB03317	Heme C	Small molecule

Gene-centered ligand-gene interaction network

Ligands binding to mutated ligand binding site of CYP2C9 go to BioLip

Ligand ID	Ligand short name	Ligand long name	PDB ID	PDB name	mutLBS
SWF		S-WARFARIN	1og5	A	F100 L102 A103 T364
SWF		S-WARFARIN	1og5	B	F100 L102 A103 T364
2QJ		(2R)-N-{4-[(3-BROMOPHENYL)SULFONYL]-2-CHLOROPHENYL}-3, 3,3-TRIFLUORO-2-HYDROXY-2-METHYLPROPANAMIDE	4nz2	A	N107 L233 L362
2QJ		(2R)-N-{4-[(3-BROMOPHENYL)SULFONYL]-2-CHLOROPHENYL}-3, 3,3-TRIFLUORO-2-HYDROXY-2-METHYLPROPANAMIDE	4nz2	B	N107 L362
FLP		FLURBIPROFEN	1r9o	A	R108
HEM		HEME B	1r9o	A	W120 L362 S429 R433 E444
HEC		FERROHEME C(2-)	1og2	B	W120 R124 L362 L391 S429 R433
HEC		FERROHEME C(2-)	1og5	B	W120 R124 L362 L391 S429 R433 E444
HEC		FERROHEME C(2-)	1og5	A	W120 R124 L362 S429 R433
HEM		HEME B	4nz2	A	W120 R124 L362 S429 R433
HEM		HEME B	4nz2	B	W120 R124 L362 S429 R433
HEC		FERROHEME C(2-)	1og2	A	W120 R124 L362 S429 R433 E444

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Conservation information for LBS of CYP2C9

Multiple alignments for P11712 in multiple species

LBS

AA sequence

# species

Species