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 CYP2C19

Gene summary

Basic gene Info.	Gene symbol	CYP2C19
	Gene name	cytochrome P450, family 2, subfamily C, polypeptide 19
	Synonyms	CPCJ\|CYP2C\|CYPIIC17\|CYPIIC19\|P450C2C\|P450IIC19
	Cytomap	UCSC genome browser: 10q24
	Type of gene	protein-coding
	RefGenes	NM_000769.2,
	Description	(R)-limonene 6-monooxygenase(S)-limonene 6-monooxygenase(S)-limonene 7-monooxygenaseS-mephenytoin 4-hydroxylasecytochrome P-450 II Ccytochrome P450 2C19cytochrome P450, subfamily IIC (mephenytoin 4-hydroxylase), polypeptide 19cytochrome P450-11Acy
	Modification date	20141211
dbXrefs	MIM : 124020
	HGNC : HGNC
	HPRD : 00486
Protein	UniProt: P33261 go to UniProt's Cross Reference DB Table
Expression	CleanEX: HS_CYP2C19
	BioGPS: 1557
Pathway	NCI Pathway Interaction Database: CYP2C19
	KEGG: CYP2C19
	REACTOME: CYP2C19
	Pathway Commons: CYP2C19
Context	iHOP: CYP2C19
	ligand binding site mutation search in PubMed: CYP2C19
	UCL Cancer Institute: CYP2C19
Assigned class in mutLBSgeneDB	B: This gene belongs to targetable_mutLBSgenes.

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:0042738	exogenous drug catabolic process	19029318
GO:0046483	heterocycle metabolic process	19651758
GO:0055114	oxidation-reduction process	16401082

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Ligand binding site mutations for CYP2C19

Cancer type specific mutLBS sorted by frequency

LBS	AAchange of nsSNV	Cancer type	# samples
S429,R433	G431E	SKCM	2
I178	S180F	BLCA	1
I362	I362V	COAD	1
D293	A292P	COAD	1
R433	R433W	COAD	1
A441	R442H	COAD	1
L366	L366P	COAD	1
A441	R442H	GBM	1
W120	W120L	LUAD	1
Q356	E354K	LUAD	1
A441	R442L	LUAD	1
Q356	R357I	LUAD	1
S365	S365R	LUSC	1
L366	L366M	LUSC	1
L366	L366Q	OV	1
E444	L445Q	OV	1
L361	D360N	SKCM	1
L391	S393F	SKCM	1
W120	R119K	SKCM	1
R433	R433Q	SKCM	1
L361	D360E	SKCM	1
G437	G437E	SKCM	1
L391	S390F	SKCM	1
E300	E300K	SKCM	1
T305	R307S	SKCM	1
I178	V177M	STAD	1
R124	R125H	STAD	1
L391	T389I	STAD	1
P427	P427R	STAD	1
R124	R125H	UCEC	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 CYP2C19

Protein structure of wild type (WT) and mutant type (MT) of CYP2C19

Wild type CYP2C19

Mutant type CYP2C19

Free energy of binding of drugs to wild type and mutant tpye of CYP2C19

Gene symbol	Drug name	Free energy of binding (kcal/mol) of wild type	Free energy of binding (kcal/mol) of mutant type
CYP2C19	Fluvoxamine	-6.9	-7.1
CYP2C19	Isoniazid	-6	-6
CYP2C19	moclobemide	-6.7	-7.5

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
G437	G437E	0.27001735
L391	S393F	0.25655226
T305	R307S	-1.5057434
I362	I362V	-1.4135153
A441	R442H	-1.4031014
L366	L366Q	-1.1979895
E444	L445Q	-1.1947298
Q356	R357I	-1.1410507
L366	L366P	-1.0238592
W120	R119K	-1.0221671
R124	R125H	-0.97806469
I178	V177M	-0.93918749
Q356	E354K	-0.93467829
L361	D360N	-0.92639647
R433	G431E	-0.87435855
S429	G431E	-0.87435855
L366	L366M	-0.86037486
R433	R433Q	-0.85266388
W120	W120L	-0.7385728
A441	R442L	-0.68061755
I178	S180F	-0.62374496
R433	R433W	-0.56910267
L391	S390F	-0.54231976
D293	A292P	-0.51599665
L361	D360E	-0.51264402
S365	S365R	-0.37463172
L391	T389I	-0.36248189
E300	E300K	-0.25952443
P427	P427R	-0.23443936

(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 CYP2C19 from PDB

PDB ID	PDB title	PDB structure
4GQS	Structure of Human Microsomal Cytochrome P450 (CYP) 2C19

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Differential gene expression and gene-gene network for CYP2C19

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 CYP2C19 and the right PPI network was created from samples without mutations in the LBS of CYP2C19. 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 CYP2C19

Gene level disease information (DisGeNet)

Disease ID	Disease name	# PubMed	Association type
umls:C0007222	Cardiovascular Diseases	12	Biomarker, GeneticVariation
umls:C0040053	Thrombosis	4	Biomarker, GeneticVariation
umls:C0860207	Drug-Induced Liver Injury	3	Biomarker, GeneticVariation
umls:C0033578	Prostatic Neoplasms	2	Biomarker, GeneticVariation
umls:C0085215	Primary Ovarian Insufficiency	1	Biomarker, GeneticVariation
umls:C0022661	Kidney Failure, Chronic	1	Biomarker
umls:C2609414	Acute Kidney Injury	1	Biomarker

Mutation level pathogenic information (ClinVar annotation)

Allele ID	AA change	Clinical significance	Origin	Phenotype IDs
31937	R433W	drug response	Germline	MedGen:C1836024

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Pharmacological information for CYP2C19

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
Approved	DB00951	Isoniazid	Small molecule

Gene-centered ligand-gene interaction network

Ligands binding to mutated ligand binding site of CYP2C19 go to BioLip

Ligand ID	Ligand short name	Ligand long name	PDB ID	PDB name	mutLBS
0XV		(4-HYDROXY-3,5-DIMETHYLPHENYL)(2-METHYL-1-BENZOFURAN-3- YL)METHANONE	4gqs	A	D293 E300 I362 L366
0XV		(4-HYDROXY-3,5-DIMETHYLPHENYL)(2-METHYL-1-BENZOFURAN-3- YL)METHANONE	4gqs	B	D293 E300 I362 L366
0XV		(4-HYDROXY-3,5-DIMETHYLPHENYL)(2-METHYL-1-BENZOFURAN-3- YL)METHANONE	4gqs	C	D293 E300 I362 L366
0XV		(4-HYDROXY-3,5-DIMETHYLPHENYL)(2-METHYL-1-BENZOFURAN-3- YL)METHANONE	4gqs	D	D293 E300 I362 L366
HEM		HEME B	4gqs	C	W120 R124 I178 T305 I362 S365 L391 P427 S429 R433 G437 A441 E444
HEM		HEME B	4gqs	D	W120 R124 Q356 L361 I362 S365 P427 S429 R433 G437 A441
HEM		HEME B	4gqs	B	W120 R124 T305 L361 I362 S365 P427 S429 R433 G437 A441
HEM		HEME B	4gqs	A	W120 R124 T305 S365 L366 P427 S429 R433 G437 A441

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Conservation information for LBS of CYP2C19

Multiple alignments for P33261 in multiple species

LBS

AA sequence

# species

Species