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 BTK

Gene summary

Basic gene Info.	Gene symbol	BTK
	Gene name	Bruton agammaglobulinemia tyrosine kinase
	Synonyms	AGMX1\|AT\|ATK\|BPK\|IMD1\|PSCTK1\|XLA
	Cytomap	UCSC genome browser: Xq21.33-q22
	Type of gene	protein-coding
	RefGenes	NM_000061.2, NM_001287344.1,NM_001287345.1,
	Description	B-cell progenitor kinaseagammaglobulinaemia tyrosine kinasedominant-negative kinase-deficient Brutons tyrosine kinasetruncated Bruton agammaglobulinemia tyrosine kinasetyrosine-protein kinase BTKtyrosine-protein kinase BTK isoform (lacking exon 14)
	Modification date	20141221
dbXrefs	MIM : 300300
	HGNC : HGNC
	Ensembl : ENSG00000010671
	HPRD : 02248
	Vega : OTTHUMG00000022022
Protein	UniProt: Q06187 go to UniProt's Cross Reference DB Table
Expression	CleanEX: HS_BTK
	BioGPS: 695
Pathway	NCI Pathway Interaction Database: BTK
	KEGG: BTK
	REACTOME: BTK
	Pathway Commons: BTK
Context	iHOP: BTK
	ligand binding site mutation search in PubMed: BTK
	UCL Cancer Institute: BTK
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

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Ligand binding site mutations for BTK

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
K53	S51N	COAD	1
K12	L11V	LUAD	1
T474	T474S	LUAD	1
C165	C165Y	LUAD	1
Y476	Y476N	LUAD	1
H143	C145S	LUAD	1
C155	Q157H	LUAD	1
C154	L153F	LUAD	1
C165	Q166K	LUSC	1
C165	G164A	OV	1
L528	L528F	SKCM	1
S543	R544M	STAD	1
P22	P22H	UCEC	1
C165	I167V	UCEC	1
K26	K26N	UCEC	1
R28	R28C	UCEC	1
D539	D539N	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 BTK

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
C165	Q166K	0.27705105
Y476	Y476N	-1.7366341
L528	L528F	-1.5569193
K53	S51N	-1.2723179
H143	C145S	-1.217472
C154	L153F	-1.1354619
K12	L11V	-1.1353673
P22	P22H	-1.1235303
C165	I167V	-1.0964797
K26	K26N	-1.0696158
R28	R28C	-0.90813441
C165	G164A	-0.81945722
S543	R544M	-0.79873529
T474	T474S	-0.67947852
D539	D539N	-0.50446094
C155	Q157H	-0.41399845
C165	C165Y	-0.39709677

(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 BTK from PDB

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Differential gene expression and gene-gene network for BTK

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

Gene level disease information (DisGeNet)

Disease ID	Disease name	# PubMed	Association type
umls:C0221026	Bruton type agammaglobulinemia	119	Biomarker, GeneticVariation
umls:C0001768	Agammaglobulinemia	13	Biomarker, GeneticVariation, Therapeutic
umls:C0017661	Glomerulonephritis, IGA	1	Biomarker

Mutation level pathogenic information (ClinVar annotation)

Allele ID

AA change

Clinical significance

Origin

Phenotype IDs

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Pharmacological information for BTK

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	DB01863	Inositol 1,3,4,5-Tetrakisphosphate	Small molecule
Investigational	DB05204	XL418	Small molecule
Approved	DB09053	Ibrutinib	Small molecule

Gene-centered ligand-gene interaction network

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

Ligand ID	Ligand short name	Ligand long name	PDB ID	PDB name	mutLBS
ZN		ZINC(2+)	1b55	A	H143 C154 C155 C165
ZN		ZINC(2+)	1b55	B	H143 C154 C155 C165
ZN		ZINC(2+)	1btk	A	H143 C154 C155 C165
ZN		ZINC(2+)	1btk	B	H143 C154 C155 C165
ZN		ZINC(2+)	1bwn	A	H143 C154 C155 C165
ZN		ZINC(2+)	1bwn	B	H143 C154 C155 C165
ZN		ZINC(2+)	2z0p	A	H143 C154 C155 C165
ZN		ZINC(2+)	2z0p	B	H143 C154 C155 C165
ZN		ZINC(2+)	2z0p	C	H143 C154 C155 C165
ZN		ZINC(2+)	2z0p	D	H143 C154 C155 C165
4IP		INOSITOL 1,3,4,5-TETRAKISPHOSPHATE	1bwn	A	K12 P22 K26 R28 K53
4PT		DIC4-PHOSPHATIDYLINOSITOL(3,4,5)TRISPHOSPHATE	2z0p	A	K12 P22 K26 R28 K53
4IP		INOSITOL 1,3,4,5-TETRAKISPHOSPHATE	1b55	A	K12 P22 R28 K53
4IP		INOSITOL 1,3,4,5-TETRAKISPHOSPHATE	1bwn	B	K12 P22 R28 K53
4PT		DIC4-PHOSPHATIDYLINOSITOL(3,4,5)TRISPHOSPHATE	2z0p	B	K12 P22 R28 K53
4PT		DIC4-PHOSPHATIDYLINOSITOL(3,4,5)TRISPHOSPHATE	2z0p	D	K12 P22 R28 K53
4IP		INOSITOL 1,3,4,5-TETRAKISPHOSPHATE	1b55	B	K12 R28 K53
4PT		DIC4-PHOSPHATIDYLINOSITOL(3,4,5)TRISPHOSPHATE	2z0p	C	K12 R28 K53
4IP		INOSITOL 1,3,4,5-TETRAKISPHOSPHATE	1bwn	B	K26 K53
4IP		INOSITOL 1,3,4,5-TETRAKISPHOSPHATE	1bwn	A	K53
LHL		3-(2,6-DICHLOROPHENYL)-7-({4-[2-(DIETHYLAMINO)ETHOXY]PHENYL}AMINO)-1-METHYL-3,4-DIHYDROPYRIMIDO[4,5-D]PYRIMIDIN-2(1H)-ONE	3pj1	A	T474 L528 D539
4L6		4-AMINO-8-(5-METHYL-1H-INDAZOL-6-YL)CINNOLINE-3- CARBOXAMIDE	4z3v	A	T474 L528 D539
4RV		4-AMINO-8-(4-METHYLPYRIDIN-3-YL)CINNOLINE-3-CARBOXAMIDE	4zlz	A	T474 L528 D539
4C9		(2S)-2-({(3R)-3-[4-AMINO-3-(4-PHENOXYPHENYL)-1H- PYRAZOLO[3,4-D]PYRIMIDIN-1-YL]PIPERIDIN-1- YL}CARBONYL)-4,4-DIMETHYLPENTANENITRILE	4yhf	A	T474 Y476 D539
4C9		(2S)-2-({(3R)-3-[4-AMINO-3-(4-PHENOXYPHENYL)-1H- PYRAZOLO[3,4-D]PYRIMIDIN-1-YL]PIPERIDIN-1- YL}CARBONYL)-4,4-DIMETHYLPENTANENITRILE	4yhf	B	T474 Y476 D539
1N1		DASATINIB	3k54	A	T474 Y476 L528
1N1		DASATINIB	3oct	A	T474 Y476 L528
027		7-(4-METHYLPIPERAZIN-1-YL)-4-[(5-METHYL-1H-PYRAZOL-3-YL)AMINO]-2-(PROPAN-2-YL)PHTHALAZIN-1(2H)-ONE	3pix	A	T474 Y476 L528
03C		[5-AMINO-1-(2-METHYLPHENYL)-1H-PYRAZOL-4-YL]{3-[1-(METHYLSULFONYL)PIPERIDIN-4-YL]PHENYL}METHANONE	3piz	A	T474 Y476 L528
4RU		4-AMINOCINNOLINE-3-CARBOXAMIDE	4zly	A	T474 Y476 L528
4US		4-(2-CHLOROPHENYL)-7-[(4-METHYLPIPERAZIN-1-YL) CARBONYL]-9H-CARBAZOLE-1-CARBOXAMIDE	5bq0	A	T474 Y476 L528
B43		7-CYCLOPENTYL-5-(4-PHENOXYPHENYL)-7H-PYRROLO[2,3-D]PYRIMIDIN-4-AMINE	3gen	A	T474 Y476 L528 D539
04K		2-({4-[2-(DIETHYLAMINO)ETHOXY]PHENYL}AMINO)-6-(4-FLUOROPHENOXY)-8-METHYLPYRIDO[2,3-D]PYRIMIDIN-7(8H)-ONE	3pj2	A	T474 Y476 L528 D539
04L		2-METHYL-N-(2-PHENYL-3H-IMIDAZO[4,5-B]PYRIDIN-6-YL)-5-{[(2E)-3-PHENYLPROP-2-ENOYL]AMINO}BENZAMIDE	3pj3	A	T474 Y476 L528 D539
481		4-TERT-BUTYL-N-{3-[8-({4-[(4-METHYLPIPERAZIN-1-YL) CARBONYL]PHENYL}AMINO)IMIDAZO[1,2-A]PYRAZIN-6- YL]PHENYL}BENZAMIDE	4ot5	A	T474 Y476 L528 D539
3P0		2-{8-FLUORO-2-[2-(HYDROXYMETHYL)-3-(1-METHYL-5-{[5-(4- METHYLPIPERAZIN-1-YL)PYRIDIN-2-YL]AMINO}-6-OXO-1,6- DIHYDROPYRIDIN-3-YL)PHENYL]-1-OXO-1,2,3,4- TETRAHYDROISOQUINOLIN-6-YL}-2-METHYLPROPANENITRILE	4rg0	A	T474 Y476 L528 D539
2VL	GDC0834	N-{3-[6-({4-[(2R)-1,4-DIMETHYL-3-OXOPIPERAZIN-2- YL]PHENYL}AMINO)-4-METHYL-5-OXO-4,5-DIHYDROPYRAZIN-2- YL]-2-METHYLPHENYL}-4,5,6,7-TETRAHYDRO-1- BENZOTHIOPHENE-2-CARBOXAMIDE	4otf	A	T474 Y476 L528 D539
746		CGI1746	3ocs	A	T474 Y476 L528 D539 S543
2V2		1-{5-[3-(7-TERT-BUTYL-4-OXOQUINAZOLIN-3(4H)-YL)-2- METHYLPHENYL]-1-METHYL-2-OXO-1,2-DIHYDROPYRIDIN-3-YL}- 3-METHYLUREA	4otq	A	T474 Y476 L528 D539 S543
2V3		6-CYCLOPROPYL-2-[3-(5-{[5-(4-ETHYLPIPERAZIN-1-YL) PYRIDIN-2-YL]AMINO}-1-METHYL-6-OXO-1,6-DIHYDROPYRIDIN- 3-YL)-2-(HYDROXYMETHYL)PHENYL]-8-FLUOROISOQUINOLIN- 1(2H)-ONE	4otr	A	T474 Y476 L528 D539 S543
3OU		6-(DIMETHYLAMINO)-2-[2-(HYDROXYMETHYL)-3-(1-METHYL-5- {[5-(MORPHOLIN-4-YLCARBONYL)PYRIDIN-2-YL]AMINO}-6-OXO- 1,6-DIHYDROPYRIDIN-3-YL)PHENYL]-3,4- DIHYDROISOQUINOLIN-1(2H)-ONE	4rfy	A	T474 Y476 L528 D539 S543
3OV		6-(DIMETHYLAMINO)-8-FLUORO-2-[2-(HYDROXYMETHYL)-3-(1- METHYL-5-{[5-(MORPHOLIN-4-YLCARBONYL)PYRIDIN-2- YL]AMINO}-6-OXO-1,6-DIHYDROPYRIDIN-3-YL) PHENYL]ISOQUINOLIN-1(2H)-ONE	4rfz	A	T474 Y476 L528 D539 S543
585		6-({5-FLUORO-2-[(3,4,5-TRIMETHOXYPHENYL)AMINO]PYRIMIDIN-4-YL}AMINO)-2,2-DIMETHYL-2H-PYRIDO[3,2-B][1,4]OXAZIN-3(4H)-ONE	3piy	A	T474 Y476 L528 S543
2V1		4-(METHYLSULFONYL)-N-[3-(8-{[4-(MORPHOLIN-4- YLCARBONYL)PHENYL]AMINO}IMIDAZO[1,2-A]PYRAZIN-6-YL) PHENYL]BENZAMIDE	4ot6	A	Y476 L528
4UQ		6-{(3R)-3-[(4-TERT-BUTYLBENZOYL)AMINO]PIPERIDIN-1-YL}- 2-{[4-(MORPHOLIN-4-YLCARBONYL)PHENYL]AMINO}PYRIDINE-3- CARBOXAMIDE	5bpy	A	Y476 L528
4UQ		6-{(3R)-3-[(4-TERT-BUTYLBENZOYL)AMINO]PIPERIDIN-1-YL}- 2-{[4-(MORPHOLIN-4-YLCARBONYL)PHENYL]AMINO}PYRIDINE-3- CARBOXAMIDE	5bpy	B	Y476 L528
3YO		N-(6-FLUORO-2-METHYL-3-{5-[(5-METHYL-4,5,6,7- TETRAHYDROPYRAZOLO[1,5-A]PYRAZIN-2-YL)AMINO]-6-OXO-1, 6-DIHYDROPYRIDAZIN-3-YL}PHENYL)-1-BENZOTHIOPHENE-2- CARBOXAMIDE	4rx5	A	Y476 L528 D539
2P5		4-TERT-BUTYL-N-[2-METHYL-3-(6-{[4-(MORPHOLIN-4- YLCARBONYL)PHENYL]AMINO}-7H-PURIN-2-YL) PHENYL]BENZAMIDE	4nwm	A	Y476 L528 D539 S543
2P5		4-TERT-BUTYL-N-[2-METHYL-3-(6-{[4-(MORPHOLIN-4- YLCARBONYL)PHENYL]AMINO}-7H-PURIN-2-YL) PHENYL]BENZAMIDE	4nwm	B	Y476 L528 D539 S543

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Conservation information for LBS of BTK

Multiple alignments for Q06187 in multiple species

LBS

AA sequence

# species

Species