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 KEAP1

Gene summary

Basic gene Info.	Gene symbol	KEAP1
	Gene name	kelch-like ECH-associated protein 1
	Synonyms	INrf2\|KLHL19
	Cytomap	UCSC genome browser: 19p13.2
	Type of gene	protein-coding
	RefGenes	NM_012289.3, NM_203500.1,
	Description	cytosolic inhibitor of Nrf2kelch-like family member 19kelch-like protein 19
	Modification date	20141207
dbXrefs	MIM : 606016
	HGNC : HGNC
	Ensembl : ENSG00000079999
	HPRD : 12079
	Vega : OTTHUMG00000180579
Protein	UniProt: Q14145 go to UniProt's Cross Reference DB Table
Expression	CleanEX: HS_KEAP1
	BioGPS: 9817
Pathway	NCI Pathway Interaction Database: KEAP1
	KEGG: KEAP1
	REACTOME: KEAP1
	Pathway Commons: KEAP1
Context	iHOP: KEAP1
	ligand binding site mutation search in PubMed: KEAP1
	UCL Cancer Institute: KEAP1
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:0010499	proteasomal ubiquitin-independent protein catabolic process	15983046
GO:0016567	protein ubiquitination	15983046

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Ligand binding site mutations for KEAP1

Lollipop-style diagram of mutations at LBS in amino-acid sequence.
We represented ligand binding site mutations only. (You can see big image via clicking.)

: non-synonymous mutation on LBS, Circle size denotes number of samples.

Cancer type specific mutLBS sorted by frequency

LBS	AAchange of nsSNV	Cancer type	# samples
H154	V155F	LUSC	2
F478	G480W	LUSC	2
Y525	G524C	LUAD	1
F478	D479G	LUAD	1
G462	R460G	LUAD	1
R415	R415H	LUAD	1
H154	M156V	LUAD	1
Y334	G332C	LUAD	1
H154	V155A	LUAD	1
Y334	G333S	LUAD	1
I416	G417R	LUAD	1
G509	G509W	LUAD	1
I416	G417E	LUAD	1
R483	R483C	LUAD	1
S602	G603W	LUAD	1
R415	R415C	LUAD	1
G462	I461V	LUAD	1
F478	G480W	LUAD	1
Y334	G333C	LUAD	1
S555	R554Q	LUAD	1
S508	I506V	LUSC	1
I416	V418L	LUSC	1
H129,K131	P130L	SKCM	1
R483	R483H	STAD	1
F478	G477S	THCA	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.

Clinical information for KEAP1 from My Cancer Genome.

Kelch-like ECH-associated protein 1 (KEAP1) is a gene that encodes a protein that functions in the transportation of NF-E2-related factor 2 to the nucleus of a cell. Missense mutations, nonsense mutations, silent mutations, frameshift deletions and insertions, and in-frame deletions are observed in cancers such as intestinal cancer, lung cancer, and stomach cancer. Modified: July 1, 2015

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Protein structure related information for KEAP1

Protein structure of wild type (WT) and mutant type (MT) of KEAP1

Wild type KEAP1

Mutant type KEAP1

Free energy of binding of drugs to wild type and mutant tpye of KEAP1

Gene symbol	Drug name	Free energy of binding (kcal/mol) of wild type	Free energy of binding (kcal/mol) of mutant type
KEAP1	Dimethyl fumarate	-4	-3.7

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
H154	V155A	-1.6842836
G462	R460G	-1.573034
R415	R415H	-1.3571626
H154	V155F	-1.2574914
Y334	G333S	-1.2143485
R415	R415C	-1.123124
R483	R483H	-1.0802491
G462	I461V	-1.0482987
S555	R554Q	-1.0427242
I416	G417R	-1.041171
I416	G417E	-1.0081143
Y334	G333C	-0.95144109
S508	I506V	-0.84109019
H154	M156V	-0.83323599
R483	R483C	-0.79272534
I416	V418L	-0.61940537
F478	G477S	-0.52697565
F478	D479G	-0.5106473
K131	P130L	-0.48841152
H129	P130L	-0.48841152
Y525	G524C	-0.4367942
F478	G480W	-0.41924618
S602	G603W	-0.39342283
G509	G509W	-0.33937524
Y334	G332C	-0.33239828

(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 KEAP1 from PDB

PDB ID	PDB title	PDB structure
4ZY3	Crystal Structure of Keap1 in Complex with a small chemical compound, K67

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Differential gene expression and gene-gene network for KEAP1

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

KEAP1_LUAD_DE

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 KEAP1 and the right PPI network was created from samples without mutations in the LBS of KEAP1. Only genes with p-value < 0.05 are shown.
Red circle: input gene. Orange circle: LBSgene. Blue circle: other gene.

* In LUAD

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Phenotype information for KEAP1

Gene level disease information (DisGeNet)

Disease ID	Disease name	# PubMed	Association type
umls:C0007131	Carcinoma, Non-Small-Cell Lung	13	Biomarker
umls:C0016978	Gallbladder Neoplasms	1	Biomarker, GeneticVariation
umls:C0007134	Carcinoma, Renal Cell	1	Biomarker
umls:C0242656	Disease Progression	1	Biomarker
umls:C0017178	Gastrointestinal Diseases	1	Biomarker
umls:C0019158	Hepatitis	1	Biomarker
umls:C0022593	Keratosis	1	Biomarker

Mutation level pathogenic information (ClinVar annotation)

Allele ID

AA change

Clinical significance

Origin

Phenotype IDs

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Pharmacological information for KEAP1

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\|investigational	DB08908	Dimethyl fumarate	Small molecule

Gene-centered ligand-gene interaction network

Ligands binding to mutated ligand binding site of KEAP1 go to BioLip

Ligand ID	Ligand short name	Ligand long name	PDB ID	PDB name	mutLBS
SXJ		(13ALPHA,18ALPHA)-2-CYANO-3-HYDROXY-12- OXOOLEANA-2,9(11)-DIEN-28-OIC ACID	4cxt	A	H129 K131 H154
4ID		2-({5-[(2,4-DIMETHYLPHENYL)SULFONYL]-6-OXO-1,6- DIHYDROPYRIMIDIN-2-YL}SULFANYL)-N-[2- (TRIFLUOROMETHYL)PHENYL]ACETAMIDE	4in4	A	R415 F478 R483 S508 Y525 S555
4ID		2-({5-[(2,4-DIMETHYLPHENYL)SULFONYL]-6-OXO-1,6- DIHYDROPYRIMIDIN-2-YL}SULFANYL)-N-[2- (TRIFLUOROMETHYL)PHENYL]ACETAMIDE	4in4	B	R415 F478 R483 S508 Y525 S555
4ID		2-({5-[(2,4-DIMETHYLPHENYL)SULFONYL]-6-OXO-1,6- DIHYDROPYRIMIDIN-2-YL}SULFANYL)-N-[2- (TRIFLUOROMETHYL)PHENYL]ACETAMIDE	4in4	C	R415 F478 R483 S508 Y525 S555
41P		2,2'-(NAPHTHALENE-1,4-DIYLBIS(((4-METHOXYPHENYL) SULFONYL)AZANEDIYL))DIACETAMIDE	4xmb	A	Y334 R415 G462 F478 S508 G509 Y525 S555 S602
1VX		(1S,2R)-2-{[(1S)-5-METHYL-1-[(1-OXO-1,3-DIHYDRO-2H- ISOINDOL-2-YL)METHYL]-3,4-DIHYDROISOQUINOLIN-2(1H)- YL]CARBONYL}CYCLOHEXANECARBOXYLIC ACID	4l7d	A	Y334 R415 G462 G509 S602
4ID		2-({5-[(2,4-DIMETHYLPHENYL)SULFONYL]-6-OXO-1,6- DIHYDROPYRIMIDIN-2-YL}SULFANYL)-N-[2- (TRIFLUOROMETHYL)PHENYL]ACETAMIDE	4in4	A	Y334 R415 G509 S602
4ID		2-({5-[(2,4-DIMETHYLPHENYL)SULFONYL]-6-OXO-1,6- DIHYDROPYRIMIDIN-2-YL}SULFANYL)-N-[2- (TRIFLUOROMETHYL)PHENYL]ACETAMIDE	4in4	B	Y334 R415 G509 S602
4ID		2-({5-[(2,4-DIMETHYLPHENYL)SULFONYL]-6-OXO-1,6- DIHYDROPYRIMIDIN-2-YL}SULFANYL)-N-[2- (TRIFLUOROMETHYL)PHENYL]ACETAMIDE	4in4	C	Y334 R415 G509 S602
12O		(1R,2R)-2-{[(1S)-1-[(1,3-DIOXO-1,3-DIHYDRO-2H-ISOINDOL- 2-YL)METHYL]-3,4-DIHYDROISOQUINOLIN-2(1H)- YL]CARBONYL}CYCLOHEXANECARBOXYLIC ACID	4ifn	X	Y334 R415 G509 S602
1VV		(1S,2R)-2-{[(1S)-1-[(1,3-DIOXO-1,3-DIHYDRO-2H-ISOINDOL- 2-YL)METHYL]-3,4-DIHYDROISOQUINOLIN-2(1H)- YL]CARBONYL}CYCLOHEXANECARBOXYLIC ACID	4l7b	B	Y334 R415 G509 S602
1VW		2-{[(1S)-2-{[(1R,2S)-2-(1H-TETRAZOL-5-YL) CYCLOHEXYL]CARBONYL}-1,2,3,4-TETRAHYDROISOQUINOLIN-1- YL]METHYL}-1H-ISOINDOLE-1,3(2H)-DIONE	4l7c	A	Y334 R415 G509 S602
1VW		2-{[(1S)-2-{[(1R,2S)-2-(1H-TETRAZOL-5-YL) CYCLOHEXYL]CARBONYL}-1,2,3,4-TETRAHYDROISOQUINOLIN-1- YL]METHYL}-1H-ISOINDOLE-1,3(2H)-DIONE	4l7c	B	Y334 R415 G509 S602
1VW		2-{[(1S)-2-{[(1R,2S)-2-(1H-TETRAZOL-5-YL) CYCLOHEXYL]CARBONYL}-1,2,3,4-TETRAHYDROISOQUINOLIN-1- YL]METHYL}-1H-ISOINDOLE-1,3(2H)-DIONE	4l7c	C	Y334 R415 G509 S602
1VX		(1S,2R)-2-{[(1S)-5-METHYL-1-[(1-OXO-1,3-DIHYDRO-2H- ISOINDOL-2-YL)METHYL]-3,4-DIHYDROISOQUINOLIN-2(1H)- YL]CARBONYL}CYCLOHEXANECARBOXYLIC ACID	4l7d	B	Y334 R415 G509 S602
1VX		(1S,2R)-2-{[(1S)-5-METHYL-1-[(1-OXO-1,3-DIHYDRO-2H- ISOINDOL-2-YL)METHYL]-3,4-DIHYDROISOQUINOLIN-2(1H)- YL]CARBONYL}CYCLOHEXANECARBOXYLIC ACID	4l7d	C	Y334 R415 G509 S602
2FS		(1S,2R)-2-{[(1S)-1-[(1-OXO-1,3-DIHYDRO-2H-ISOINDOL-2- YL)METHYL]-3,4-DIHYDROISOQUINOLIN-2(1H)- YL]CARBONYL}CYCLOHEXANECARBOXYLIC ACID	4n1b	A	Y334 R415 G509 S602
2FS		(1S,2R)-2-{[(1S)-1-[(1-OXO-1,3-DIHYDRO-2H-ISOINDOL-2- YL)METHYL]-3,4-DIHYDROISOQUINOLIN-2(1H)- YL]CARBONYL}CYCLOHEXANECARBOXYLIC ACID	4n1b	B	Y334 R415 G509 S602
2FS		(1S,2R)-2-{[(1S)-1-[(1-OXO-1,3-DIHYDRO-2H-ISOINDOL-2- YL)METHYL]-3,4-DIHYDROISOQUINOLIN-2(1H)- YL]CARBONYL}CYCLOHEXANECARBOXYLIC ACID	4n1b	C	Y334 R415 G509 S602
IQK		N,N'-NAPHTHALENE-1,4-DIYLBIS(4- METHOXYBENZENESULFONAMIDE)	4iqk	A	Y334 R415 R483 S508 G509 Y525 S555 S602
III		Peptide ligand (GLY,ASP,GLU,GLU,THR,GLY,GLU)	3zgc	A	Y334 R415 R483 S508 G509 Y525 S555 S602
III		Peptide ligand (ALA,PHE,PHE,ALA,GLN,LEU,GLN,LEU,ASP,GLU,GLU,THR,GLY,GLU,PHE,LEU)	2flu	X	Y334 R415 R483 S508 Y525 S555 S602
III		Peptide ligand (ALA,PHE,PHE,ALA,GLN,LEU,GLN,LEU,ASP,GLU,GLU,THR,GLY,GLU,PHE,LEU)	4ifl	X	Y334 R415 R483 S508 Y525 S555 S602

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Conservation information for LBS of KEAP1

Multiple alignments for Q14145 in multiple species

LBS

AA sequence

# species

Species