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 TYK2

Gene summary

Basic gene Info.	Gene symbol	TYK2
	Gene name	tyrosine kinase 2
	Synonyms	IMD35\|JTK1
	Cytomap	UCSC genome browser: 19p13.2
	Type of gene	protein-coding
	RefGenes	NM_003331.4,
	Description	non-receptor tyrosine-protein kinase TYK2
	Modification date	20141221
dbXrefs	MIM : 176941
	HGNC : HGNC
	Ensembl : ENSG00000105397
	HPRD : 01490
	Vega : OTTHUMG00000166373
Protein	UniProt: P29597 go to UniProt's Cross Reference DB Table
Expression	CleanEX: HS_TYK2
	BioGPS: 7297
Pathway	NCI Pathway Interaction Database: TYK2
	KEGG: TYK2
	REACTOME: TYK2
	Pathway Commons: TYK2
Context	iHOP: TYK2
	ligand binding site mutation search in PubMed: TYK2
	UCL Cancer Institute: TYK2
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 TYK2.	1. "Staerk J, Kallin A, Royer Y, Diaconu CC, Dusa A, Demoulin JB, Vainchenker W,Constantinescu SN. JAK2, the JAK2 V617F mutant and cytokine receptors. Pathol Biol (Paris). 2007 Mar;55(2):88-91. Epub 2006 Aug 14" 16904848 2. "Gakovic M, Ragimbeau J, Francois V, Constantinescu SN, Pellegrini S. The Stat3-activating Tyk2 V678F mutant does not up-regulate signaling through the type I interferon receptor but confers ligand hypersensitivity to a homodimeric receptor. J Biol Chem. 2008 Jul 4;283(27):18522-9. doi: 10.1074/jbc.M801427200. Epub 2008 May 2." 18456658

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 TYK2

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
N734	H732R	COAD	1
R503	R501W	GBM	1
C536	G535D	HNSC	1
D1041	D1041A	KIRC	1
R521	S522F	SKCM	1
K930,A928	V929M	UCEC	1
G906,F908	H907N	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 TYK2

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
R521	S522F	0.2181314
D1041	D1041A	-0.92266415
G906	H907N	-0.86186515
F908	H907N	-0.86186515
A928	V929M	-0.81962878
K930	V929M	-0.81962878
R503	R501W	-0.80277644
N734	H732R	-0.4757276
C536	G535D	-0.21016693

(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 TYK2 from PDB

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Differential gene expression and gene-gene network for TYK2

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 TYK2 and the right PPI network was created from samples without mutations in the LBS of TYK2. 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 TYK2

Gene level disease information (DisGeNet)

Disease ID	Disease name	# PubMed	Association type
umls:C0026769	Multiple Sclerosis	8	Biomarker, GeneticVariation
umls:C0033860	Psoriasis	4	Biomarker, GeneticVariation
umls:C0010346	Crohn Disease	3	Biomarker, GeneticVariation
umls:C0003873	Arthritis, Rheumatoid	3	Biomarker, GeneticVariation
umls:C1969086	Tyrosine Kinase 2 Deficiency	1	Biomarker, GeneticVariation
umls:C0236736	Cocaine-Related Disorders	1	Biomarker
umls:C0023892	Liver Cirrhosis, Biliary	1	Biomarker
umls:C1456784	Paranoid Disorders	1	Biomarker

Mutation level pathogenic information (ClinVar annotation)

Allele ID

AA change

Clinical significance

Origin

Phenotype IDs

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Pharmacological information for TYK2

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	DB04716	2-(1,1-DIMETHYLETHYL)9-FLUORO-3,6-DIHYDRO-7H-BENZ[H]-IMIDAZ[4,5-F]ISOQUINOLIN-7-ONE	Small molecule
Experimental	DB08183	3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile	Small molecule

Gene-centered ligand-gene interaction network

Ligands binding to mutated ligand binding site of TYK2 go to BioLip

Ligand ID	Ligand short name	Ligand long name	PDB ID	PDB name	mutLBS
5U3		3-AZANYL-5-[(2~{S})-3-METHYLBUTAN-2-YL]-7-[1-METHYL-5- (2-OXIDANYLPROPAN-2-YL)PYRAZOL-3-YL]-1~{H}-PYRAZOLO[4, 3-C]PYRIDIN-4-ONE	5f1z	A	A928
0X6		2,6-DICHLORO-4-CYANO-N-{2-[(CYCLOPROPYLCARBONYL) AMINO]PYRIDIN-4-YL}BENZAMIDE	4gii	A	A928 D1041
0XH		2,6-DICHLORO-N-[2-({[(1R,2R)-2- FLUOROCYCLOPROPYL]CARBONYL}AMINO)PYRIDIN-4- YL]BENZAMIDE	4gj2	A	A928 D1041
0XP		2,6-DICHLORO-4-CYANO-N-[2-({[(1R,2R)-2- FLUOROCYCLOPROPYL]CARBONYL}AMINO)PYRIDIN-4- YL]BENZAMIDE	4gj3	A	A928 D1041
0X5		2,6-DICHLORO-N-{2-[(CYCLOPROPYLCARBONYL)AMINO]PYRIDIN- 4-YL}BENZAMIDE	4gih	A	A928 D1041
ADP		ADP	4gvj	A	A928 K930 D1041
2YK		6-[(2,5-DIMETHOXYPHENYL)SULFANYL]-3-(1-METHYL-1H- PYRAZOL-4-YL)[1,2,4]TRIAZOLO[4,3-B]PYRIDAZINE	4py1	A	A928 K930 D1041
MG		MAGNESIUM(2+)	4gvj	A	D1041
MG		MAGNESIUM(2+)	4gvj	A	D1041
TZ1		N-{5-[(7-CHLOROQUINOLIN-4-YL)SULFANYL]-1,3,4-THIADIAZOL-2-YL}THIOPHENE-2-CARBOXAMIDE	3nyx	A	F908 A928 K930 D1041
IZA		2-(1,1-DIMETHYLETHYL)9-FLUORO-3,6-DIHYDRO-7H-BENZ[H]-IMIDAZ[4,5-F]ISOQUINOLIN-7-ONE	3lxp	A	G906 A928
0X2		2,6-DICHLORO-N-(2-OXO-2,5-DIHYDROPYRIDIN-4-YL)BENZAMIDE	4gfo	A	G906 A928
IZA		2-(1,1-DIMETHYLETHYL)9-FLUORO-3,6-DIHYDRO-7H-BENZ[H]-IMIDAZ[4,5-F]ISOQUINOLIN-7-ONE	3nz0	A	G906 A928 D1041
5U4		3-AZANYL-5-(2-METHYLPHENYL)-7-(1-METHYLPYRAZOL-3-YL)- 1~{H}-PYRAZOLO[4,3-C]PYRIDIN-4-ONE	5f20	A	G906 A928 D1041
MI1		CP-690,550	3lxn	A	G906 A928 K930 D1041
2TT		2-CHLORO-N-{2-[(CYCLOPROPYLCARBONYL)AMINO]PYRIDIN-4- YL}BENZAMIDE	4oli	A	G906 D1041
AGS		ADENOSINE 5'-[GAMMA-THIO]TRIPHOSPHATE	5c03	A	N734
AGS		ADENOSINE 5'-[GAMMA-THIO]TRIPHOSPHATE	5c03	B	N734
III		Peptide ligand (ASN,LEU,LEU,LEU,SER,THR,SER,GLU,GLU,GLN,ILE,GLU,LYS,CYS,PHE,ILE,ILE,GLU,ASN)	4po6	A	R503 R521 C536

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Conservation information for LBS of TYK2

Multiple alignments for P29597 in multiple species

LBS

AA sequence

# species

Species