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 CXCR4

Gene summary

Basic gene Info.	Gene symbol	CXCR4
	Gene name	chemokine (C-X-C motif) receptor 4
	Synonyms	CD184\|D2S201E\|FB22\|HM89\|HSY3RR\|LAP-3\|LAP3\|LCR1\|LESTR\|NPY3R\|NPYR\|NPYRL\|NPYY3R\|WHIM
	Cytomap	UCSC genome browser: 2q21
	Type of gene	protein-coding
	RefGenes	NM_001008540.1, NM_003467.2,
	Description	C-X-C chemokine receptor type 4CD184 antigenLPS-associated protein 3SDF-1 receptorfusinleukocyte-derived seven transmembrane domain receptorlipopolysaccharide-associated protein 3neuropeptide Y receptor Y3seven transmembrane helix receptorseven-t
	Modification date	20141221
dbXrefs	MIM : 162643
	HGNC : HGNC
	Ensembl : ENSG00000121966
	HPRD : 01217
	Vega : OTTHUMG00000153583
Protein	UniProt: P61073 go to UniProt's Cross Reference DB Table
Expression	CleanEX: HS_CXCR4
	BioGPS: 7852
Pathway	NCI Pathway Interaction Database: CXCR4
	KEGG: CXCR4
	REACTOME: CXCR4
	Pathway Commons: CXCR4
Context	iHOP: CXCR4
	ligand binding site mutation search in PubMed: CXCR4
	UCL Cancer Institute: CXCR4
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 CXCR4.	1. "Wong RS, Bodart V, Metz M, Labrecque J, Bridger G, Fricker SP. Comparison of the potential multiple binding modes of bicyclam, monocylam, and noncyclam small-molecule CXC chemokine receptor 4 inhibitors. Mol Pharmacol. 2008 Dec;74(6):1485-95. doi: 10.1124/mol.108.049775. Epub 2008 Sep 2. PubMed PMID: 18768385. " 18768385 2. "Thiele S, Mungalpara J, Steen A, Rosenkilde MM, Våbenø J. Determination of the binding mode for the cyclopentapeptide CXCR4 antagonist FC131 using a dual approach of ligand modifications and receptor mutagenesis. Br J Pharmacol. 2014 Dec;171(23):5313-29. doi: 10.1111/bph.12842. PubMed PMID: 25039237; PubMed Central PMCID: PMC4294042. " 25039237

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

GO ID	GO Term	PubMed ID
GO:0007186	G-protein coupled receptor signaling pathway	10644702
GO:0071345	cellular response to cytokine stimulus	21540189

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Ligand binding site mutations for CXCR4

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
R183	R183K	BLCA	1
H113	H113R	COAD	1
R183	D181N	COAD	1
W94	P92S	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 CXCR4

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
R183	R183K	-1.5337169
R183	D181N	-0.97323554
W94	P92S	-0.97060764
H113	H113R	-0.099349814

(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 CXCR4 from PDB

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Differential gene expression and gene-gene network for CXCR4

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 CXCR4 and the right PPI network was created from samples without mutations in the LBS of CXCR4. 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 CXCR4

Gene level disease information (DisGeNet)

Disease ID	Disease name	# PubMed	Association type
umls:C0027627	Neoplasm Metastasis	195	AlteredExpression, Biomarker, GeneticVariation
umls:C0472817	WHIM syndrome	33	Biomarker, GeneticVariation
umls:C0007621	Cell Transformation, Neoplastic	1	Biomarker
umls:C0027796	Neuralgia	1	Biomarker

Mutation level pathogenic information (ClinVar annotation)

Allele ID

AA change

Clinical significance

Origin

Phenotype IDs

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Pharmacological information for CXCR4

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	DB00452	Framycetin	Small molecule
Investigational	DB05501	AMD-070	Small molecule
Approved	DB06809	Plerixafor	Small molecule

Gene-centered ligand-gene interaction network

Ligands binding to mutated ligand binding site of CXCR4 go to BioLip

Ligand ID	Ligand short name	Ligand long name	PDB ID	PDB name	mutLBS
ITD		(6,6-DIMETHYL-5,6-DIHYDROIMIDAZO[2,1-B][1,3]THIAZOL-3-YL)METHYL N,N'-DICYCLOHEXYLIMIDOTHIOCARBAMATE	3oe8	A	W94
ITD		(6,6-DIMETHYL-5,6-DIHYDROIMIDAZO[2,1-B][1,3]THIAZOL-3-YL)METHYL N,N'-DICYCLOHEXYLIMIDOTHIOCARBAMATE	3oe9	A	W94 H113 R183
ITD		(6,6-DIMETHYL-5,6-DIHYDROIMIDAZO[2,1-B][1,3]THIAZOL-3-YL)METHYL N,N'-DICYCLOHEXYLIMIDOTHIOCARBAMATE	3oe9	B	W94 H113 R183
ITD		(6,6-DIMETHYL-5,6-DIHYDROIMIDAZO[2,1-B][1,3]THIAZOL-3-YL)METHYL N,N'-DICYCLOHEXYLIMIDOTHIOCARBAMATE	3odu	A	W94 R183
ITD		(6,6-DIMETHYL-5,6-DIHYDROIMIDAZO[2,1-B][1,3]THIAZOL-3-YL)METHYL N,N'-DICYCLOHEXYLIMIDOTHIOCARBAMATE	3odu	B	W94 R183
ITD		(6,6-DIMETHYL-5,6-DIHYDROIMIDAZO[2,1-B][1,3]THIAZOL-3-YL)METHYL N,N'-DICYCLOHEXYLIMIDOTHIOCARBAMATE	3oe6	A	W94 R183
ITD		(6,6-DIMETHYL-5,6-DIHYDROIMIDAZO[2,1-B][1,3]THIAZOL-3-YL)METHYL N,N'-DICYCLOHEXYLIMIDOTHIOCARBAMATE	3oe8	B	W94 R183
ITD		(6,6-DIMETHYL-5,6-DIHYDROIMIDAZO[2,1-B][1,3]THIAZOL-3-YL)METHYL N,N'-DICYCLOHEXYLIMIDOTHIOCARBAMATE	3oe8	C	W94 R183

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Conservation information for LBS of CXCR4

Multiple alignments for P61073 in multiple species

LBS	AA sequence	# species	Species
C186	DDRYICDRFYP	4	Homo sapiens, Canis lupus familiaris, Pan troglodytes, Macaca mulatta
C186	NGQFVCDRIYP	1	Xenopus tropicalis
C186	DDRYICDRLYP	1	Mus musculus
C186	DERYICDRFYP	1	Bos taurus
D187	DRYICDRFYP-	4	Homo sapiens, Canis lupus familiaris, Pan troglodytes, Macaca mulatta
D187	GQFVCDRIYPI	1	Xenopus tropicalis
D187	DRYICDRLYP-	1	Mus musculus
D187	ERYICDRFYP-	1	Bos taurus
D97	PFWAVDAVANW	4	Homo sapiens, Bos taurus, Pan troglodytes, Macaca mulatta
D97	PFWSVDAAIGW	1	Xenopus tropicalis
D97	PFWAVDAMADW	1	Mus musculus
D97	PFWAVEAVANW	1	Canis lupus familiaris
E288	WISITEALAFF	6	Homo sapiens, Mus musculus, Bos taurus, Canis lupus familiaris, Pan troglodytes, Macaca mulatta
E288	AISITEALAFF	1	Xenopus tropicalis
E32	PCFREENAHFN	3	Bos taurus, Canis lupus familiaris, Macaca mulatta
E32	PCFREENANFN	2	Homo sapiens, Pan troglodytes
E32	PCFMHDNSDFN	1	Xenopus tropicalis
E32	PCFRDENVHFN	1	Mus musculus
H113	LCKAVHVIYTV	6	Homo sapiens, Xenopus tropicalis, Bos taurus, Canis lupus familiaris, Pan troglodytes, Macaca mulatta
H113	LCKAVHIIYTV	1	Mus musculus
I185	ADDRYICDRFY	4	Homo sapiens, Canis lupus familiaris, Pan troglodytes, Macaca mulatta
I185	ENGQFVCDRIY	1	Xenopus tropicalis
I185	GDDRYICDRLY	1	Mus musculus
I185	VDERYICDRFY	1	Bos taurus
K38	NAHFNRIFLPT	3	Bos taurus, Canis lupus familiaris, Macaca mulatta
K38	NANFNKIFLPT	2	Homo sapiens, Pan troglodytes
K38	NSDFNRIFLPT	1	Xenopus tropicalis
K38	NVHFNRIFLPT	1	Mus musculus
R183	SEADDRYICDR	3	Homo sapiens, Pan troglodytes, Macaca mulatta
R183	SDENGQFVCDR	1	Xenopus tropicalis
R183	SQGDDRYICDR	1	Mus musculus
R183	KEVDERYICDR	1	Bos taurus
R183	READDRYICDR	1	Canis lupus familiaris
R188	RYICDRFYP--	5	Homo sapiens, Bos taurus, Canis lupus familiaris, Pan troglodytes, Macaca mulatta
R188	QFVCDRIYPID	1	Xenopus tropicalis
R188	RYICDRLYP--	1	Mus musculus
V112	FLCKAVHVIYT	6	Homo sapiens, Xenopus tropicalis, Bos taurus, Canis lupus familiaris, Pan troglodytes, Macaca mulatta
V112	FLCKAVHIIYT	1	Mus musculus
W102	DAVANWYFGNF	3	Homo sapiens, Pan troglodytes, Macaca mulatta
W102	DAAIGWYFKEF	1	Xenopus tropicalis
W102	DAMADWYFGKF	1	Mus musculus
W102	DAVANWYFGKF	1	Bos taurus
W102	EAVANWYFGNF	1	Canis lupus familiaris
W94	ITLPFWAVDAV	3	Homo sapiens, Pan troglodytes, Macaca mulatta
W94	FTLPFWSVDAA	1	Xenopus tropicalis
W94	ITLPFWAVDAM	1	Mus musculus
W94	LTLPFWAVDAV	1	Bos taurus
W94	LTLPFWAVEAV	1	Canis lupus familiaris
Y116	AVHVIYTVNLY	6	Homo sapiens, Xenopus tropicalis, Bos taurus, Canis lupus familiaris, Pan troglodytes, Macaca mulatta
Y116	AVHIIYTVNLY	1	Mus musculus