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 ALK

Gene summary

Basic gene Info.	Gene symbol	ALK
	Gene name	anaplastic lymphoma receptor tyrosine kinase
	Synonyms	CD246\|NBLST3
	Cytomap	UCSC genome browser: 2p23
	Type of gene	protein-coding
	RefGenes	NM_004304.4,
	Description	ALK tyrosine kinase receptorCD246 antigenmutant anaplastic lymphoma kinase
	Modification date	20141222
dbXrefs	MIM : 105590
	HGNC : HGNC
	Ensembl : ENSG00000171094
	HPRD : 00104
	Vega : OTTHUMG00000152034
Protein	UniProt: Q9UM73 go to UniProt's Cross Reference DB Table
Expression	CleanEX: HS_ALK
	BioGPS: 238
Pathway	NCI Pathway Interaction Database: ALK
	KEGG: ALK
	REACTOME: ALK
	Pathway Commons: ALK
Context	iHOP: ALK
	ligand binding site mutation search in PubMed: ALK
	UCL Cancer Institute: ALK
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 ALK.	1. "Kanwal H, Khan MH, Rashid H. Effect of missense mutations on structure and interaction of anaplastic Lymphoma kinase (ALK) in neuroblastom. Pak J Pharm Sci. 2013 May;26(3):611-6. PubMed PMID: 23625438. " 23625438

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

GO ID	GO Term	PubMed ID
GO:0016310	phosphorylation	9174053
GO:0018108	peptidyl-tyrosine phosphorylation	9174053
GO:0046777	protein autophosphorylation	9174053

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Ligand binding site mutations for ALK

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
K1150	L1152P	COAD	1
R1275	R1275Q	COAD	1
E1210	T1211A	COAD	1
R1275	R1275L	COAD	1
K1150	T1151A	COAD	1
I1179	Q1177H	HNSC	1
F1174	F1174L	KIRC	1
G975	G977V	LUSC	1
G1269	G1269E	SKCM	1
A1200	A1200V	SKCM	1
R1253	R1253G	UCEC	1
Y1278	R1279M	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 ALK

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
G975	G977V	0.24243127
K1150	L1152P	-1.5419468
E1210	T1211A	-1.4595155
R1275	R1275Q	-1.3790775
R1253	R1253G	-1.1853061
G1269	G1269E	-0.85063045
I1179	Q1177H	-0.83307249
R1275	R1275L	-0.7650389
A1200	A1200V	-0.75650698
K1150	T1151A	-0.73901451
Y1278	R1279M	-0.50624123
F1174	F1174L	-0.45178658

(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 ALK from PDB

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Differential gene expression and gene-gene network for ALK

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

Gene level disease information (DisGeNet)

Disease ID	Disease name	# PubMed	Association type
umls:C0206180	Lymphoma, Large-Cell, Anaplastic	273	AlteredExpression, Biomarker, GeneticVariation
umls:C0007131	Carcinoma, Non-Small-Cell Lung	246	Biomarker
umls:C0027819	Neuroblastoma	89	AlteredExpression, Biomarker, GeneticVariation
umls:C0152013	Adenocarcinoma of lung	56	Biomarker
umls:C0079744	Lymphoma, Large B-Cell, Diffuse	17	AlteredExpression, Biomarker, GeneticVariation
umls:C0027627	Neoplasm Metastasis	16	Biomarker
umls:C2751681	NEUROBLASTOMA, SUSCEPTIBILITY TO, 3	4	GeneticVariation
umls:C0007134	Carcinoma, Renal Cell	4	Biomarker, GeneticVariation
umls:C0007621	Cell Transformation, Neoplastic	3	Biomarker, GeneticVariation
umls:C0278601	Inflammatory Breast Neoplasms	3	Biomarker
umls:C0018199	Granuloma, Plasma Cell	3	Biomarker
umls:C0006118	Brain Neoplasms	2	Biomarker
umls:C0085269	Plasma Cell Granuloma, Pulmonary	2	Biomarker
umls:C0027643	Neoplasm Recurrence, Local	1	Biomarker

Mutation level pathogenic information (ClinVar annotation)

Allele ID	AA change	Clinical significance	Origin	Phenotype IDs
33122	R1275Q	Pathogenic;risk factor	Somatic;unknown	GeneReviews:NBK24599 MedGen:C2751681 OMIM:613014 Orphanet:ORPHA635
214512	F1174L	Pathogenic	Somatic	GeneReviews:NBK24599 MedGen:C2751681 OMIM:613014 Orphanet:ORPHA635
214513	F1174L	Pathogenic	Somatic	GeneReviews:NBK24599 MedGen:C2751681 OMIM:613014 Orphanet:ORPHA635
214514	F1174L	Pathogenic	Somatic	GeneReviews:NBK24599 MedGen:C2751681 OMIM:613014 Orphanet:ORPHA635

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Pharmacological information for ALK

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\|nutraceutical	DB00171	Adenosine triphosphate	Small molecule
Approved	DB08865	Crizotinib	Small molecule
Approved	DB09063	Ceritinib	Small molecule
Approved	DB11363	Alectinib	Small molecule

Gene-centered ligand-gene interaction network

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

Ligand ID	Ligand short name	Ligand long name	PDB ID	PDB name	mutLBS
VGH		CRIZOTINIB	4anq	A	A1200 R1253
VGH		CRIZOTINIB	4ans	A	A1200 R1253
VGH		CRIZOTINIB	2xp2	A	A1200 R1253 G1269
VGH		CRIZOTINIB	2yfx	A	A1200 R1253 G1269
0US		N-{1-[CIS-4-(HYDROXYMETHYL)CYCLOHEXYL]-5-(PIPERIDIN-1- YLMETHYL)-1H-BENZIMIDAZOL-2-YL}-3-(PROP-2-EN-1- YLSULFAMOYL)BENZAMIDE	4fob	A	A1200 R1253 G1269
5P8		(10R)-7-AMINO-12-FLUORO-2,10,16-TRIMETHYL-15- OXO-10,15,16,17-TETRAHYDRO-2H-8,4-(METHENO) PYRAZOLO[4,3-H][2,5,11] BENZOXADIAZACYCLOTETRADECINE-3-CARBONITRILE	4cli	A	A1200 R1253 G1269
QB4		(10R)-7-AMINO-12-FLUORO-2,10,16-TRIMETHYL-15- OXO-10,15,16,17-TETRAHYDRO-2H-8,4-(METHENO) PYRAZOLO[4,3-H][2,5,11] BENZOXADIAZACYCLOTETRADECINE-3-CARBONITRILE	4clj	A	A1200 R1253 G1269
GWH		3-{(1R)-1-[2-(1,3-DIHYDRO-2H-1,2,3-TRIAZOL-2- YL)-5-FLUOROPHENYL]ETHOXY}-5-[3- (METHYLSULFONYL)PHENYL]PYRIDIN-2-AMINE	4cmt	A	A1200 R1253 G1269
J99		(10R)-7-AMINO-3-CYCLOPROPYL-12-FLUORO-1,10, 16-TRIMETHYL-16,17-DIHYDRO-1H-8,4-(METHENO) PYRAZOLO[4,3-H][2,5,11] BENZOXADIAZACYCLOTETRADECIN-15(10H)-ONE	4ctc	A	A1200 R1253 G1269
I3K		N-(4-CHLOROPHENYL)-5-[(6,7-DIMETHOXYQUINOLIN-4-YL)OXY]- 1,3-BENZOXAZOL-2-AMINE	4fny	A	G1269
0UU		METHYL CIS-4-[2-(BENZOYLAMINO)-6-(PIPERIDIN-1- YLMETHYL)-1H-BENZIMIDAZOL-1-YL]CYCLOHEXANECARBOXYLATE	4foc	A	G1269
4MK		5-CHLORO-N~2~-[5-METHYL-4-(PIPERIDIN-4-YL)-2-(PROPAN-2- YLOXY)PHENYL]-N~4~-[2-(PROPAN-2-YLSULFONYL) PHENYL]PYRIMIDINE-2,4-DIAMINE	4mkc	A	K1150 A1200
571		5-[(2R)-2-HYDROXY-2-PHENYLACETYL]-3-({[4-(4-METHYLPIPERAZIN-1-YL)PHENYL]CARBONYL}AMINO)-1,6-DIHYDROPYRROLO[3,4-C]PYRAZOL-5-IUM	2xba	A	K1150 A1200 E1210 R1253 G1269
0UV		4-FLUORO-N-{(2E)-6-{[4-(2-HYDROXYPROPAN-2-YL)PIPERIDIN- 1-YL]METHYL}-1-[CIS-4-(PROPAN-2-YLCARBAMOYL) CYCLOHEXYL]-1,3-DIHYDRO-2H-BENZIMIDAZOL-2- YLIDENE}BENZAMIDE	4fod	A	K1150 A1200 E1210 R1253 G1269
EMH		9-ETHYL-6,6-DIMETHYL-8-[4-(MORPHOLIN-4-YL)PIPERIDIN-1-YL]-11-OXO-6,11-DIHYDRO-5H-BENZO[B]CARBAZOLE-3-CARBONITRILE	3aox	A	K1150 A1200 G1269
KVC		(5R)-8-AMINO-3-FLUORO-5,19-DIMETHYL-20-OXO-5, 18,19,20-TETRAHYDRO-11,7-(AZENO)PYRIDO[2', 1':2,3]IMIDAZO[4,5-H][2,5,11] BENZOXADIAZACYCLOTETRADECINE-14-CARBONITRILE	4ctb	A	K1150 A1200 R1253 G1269
GUI		S1108_SELLECK	2xb7	A	K1150 E1210 R1253
0JF		(3S)-N-(4-METHYLBENZYL)-1-{2-[(3,4,5-TRIMETHOXYPHENYL)AMINO]PYRIMIDIN-4-YL}PIPERIDINE-3-CARBOXAMIDE	4dce	A	K1150 F1174 I1179 A1200 G1269
0JF		(3S)-N-(4-METHYLBENZYL)-1-{2-[(3,4,5-TRIMETHOXYPHENYL)AMINO]PYRIMIDIN-4-YL}PIPERIDINE-3-CARBOXAMIDE	4dce	B	K1150 F1174 I1179 A1200 G1269
NZF		(3S)-N-[3-(TRIFLUOROMETHOXY)BENZYL]-1-{2-[(3,4,5- TRIMETHOXYPHENYL)AMINO]PYRIMIDIN-4-YL}PIPERIDINE-3- CARBOXAMIDE	4fnz	A	K1150 F1174 I1179 A1200 G1269
3DK		3-[1-(2,5-DIFLUOROBENZYL)-1H-PYRAZOL-4-YL]-5-(1-METHYL- 1H-PYRAZOL-4-YL)-1H-PYRROLO[2,3-B]PYRIDINE	4joa	A	K1150 G1269 R1275
STU		STAUROSPORINE	3lcs	A	K1150 R1253
OFG		3-[(1R)-1-[5-FLUORANYL-2-(1,2,3-TRIAZOL-2-YL) PHENYL]ETHOXY]-5-(3-METHYL-1H-PYRAZOL-4-YL) PYRIDIN-2-AMINE	4ccb	A	R1253 G1269
AWF		2-(5-(6-AMINO-5-((R)-1-(5-FLUORO-2-(2H-1,2,3- TRIAZOL-2-YL)PHENYL)ETHOXY)PYRIDIN-3-YL)-4- METHYLTHIAZOL-2-YL)PROPAN-2-OL	4ccu	A	R1253 G1269
AWJ		(2R)-2-[5-(6-AMINO-5-{(1R)-1-[2-(1,3-DIHYDRO- 2H-1,2,3-TRIAZOL-2-YL)-5-FLUOROPHENYL]ETHOXY} PYRIDIN-3-YL)-4-METHYL-1,3-THIAZOL-2-YL] PROPANE-1,2-DIOL	4cd0	A	R1253 G1269
YPW		2-[(1R)-1-{[3-AMINO-6-(2-METHOXYPYRIDIN-3-YL) PYRAZIN-2-YL]OXY}ETHYL]-4-FLUORO-N-METHYLBENZAMIDE	4cmo	A	R1253 G1269
IV7		(10R)-7-AMINO-12-FLUORO-1,3,10,16- TETRAMETHYL-16,17-DIHYDRO-1H-8,4-(METHENO)PYRAZOLO[4,3 H][2,5,11]BENZOXADIAZACYCLOTETRADECIN-15(10H)- ONE	4cmu	A	R1253 G1269
3U9		3-[(1R)-1-(5-FLUORO-2-METHOXYPHENYL)ETHOXY]- 5-(1-METHYL-1H-1,2,3-TRIAZOL-5-YL)PYRIDIN-2- AMINE	4cnh	A	R1253 G1269
3U9		3-[(1R)-1-(5-FLUORO-2-METHOXYPHENYL)ETHOXY]- 5-(1-METHYL-1H-1,2,3-TRIAZOL-5-YL)PYRIDIN-2- AMINE	4cnh	B	R1253 G1269
3U9		3-[(1R)-1-(5-FLUORO-2-METHOXYPHENYL)ETHOXY]- 5-(1-METHYL-1H-1,2,3-TRIAZOL-5-YL)PYRIDIN-2- AMINE	4cnh	B	R1275 Y1278

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Conservation information for LBS of ALK

Multiple alignments for Q9UM73 in multiple species

LBS

AA sequence

# species

Species