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 EIF2AK3

Gene summary

Basic gene Info.	Gene symbol	EIF2AK3
	Gene name	eukaryotic translation initiation factor 2-alpha kinase 3
	Synonyms	PEK\|PERK\|WRS
	Cytomap	UCSC genome browser: 2p12
	Type of gene	protein-coding
	RefGenes	NM_004836.5,
	Description	PRKR-like endoplasmic reticulum kinaseeukaryotic translation initiation factor 2 alpha kinase 3hsPEKpancreatic EIF2-alpha kinase
	Modification date	20141207
dbXrefs	MIM : 604032
	HGNC : HGNC
	Ensembl : ENSG00000172071
	HPRD : 04942
	Vega : OTTHUMG00000155046
Protein	UniProt: Q9NZJ5 go to UniProt's Cross Reference DB Table
Expression	CleanEX: HS_EIF2AK3
	BioGPS: 9451
Pathway	NCI Pathway Interaction Database: EIF2AK3
	KEGG: EIF2AK3
	REACTOME: EIF2AK3
	Pathway Commons: EIF2AK3
Context	iHOP: EIF2AK3
	ligand binding site mutation search in PubMed: EIF2AK3
	UCL Cancer Institute: EIF2AK3
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:0006983	ER overload response	10677345
GO:0030968	endoplasmic reticulum unfolded protein response	10677345
GO:0046777	protein autophosphorylation	10026192

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Ligand binding site mutations for EIF2AK3

Cancer type specific mutLBS sorted by frequency

LBS	AAchange of nsSNV	Cancer type	# samples
V640	V640L	LUAD	1
K622	K622N	LUSC	1
A644	A644T	STAD	1
I651	G650R	UCEC	1
V640	K641E	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 EIF2AK3

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
V640	K641E	0.67234016
V640	V640L	-0.83523431
K622	K622N	-0.65306701
I651	G650R	-0.51370095
A644	A644T	-0.42787205

(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 EIF2AK3 from PDB

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Differential gene expression and gene-gene network for EIF2AK3

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 EIF2AK3 and the right PPI network was created from samples without mutations in the LBS of EIF2AK3. 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 EIF2AK3

Gene level disease information (DisGeNet)

Disease ID	Disease name	# PubMed	Association type
umls:C0432217	Wolcott-Rallison syndrome	21	Biomarker, GeneticVariation
umls:C0038868	Supranuclear Palsy, Progressive	1	Biomarker, GeneticVariation
umls:C0151744	Myocardial Ischemia	1	Biomarker
umls:C0038220	Status Epilepticus	1	Biomarker

Mutation level pathogenic information (ClinVar annotation)

Allele ID

AA change

Clinical significance

Origin

Phenotype IDs

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Pharmacological information for EIF2AK3

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.

Drug information targeting mutLBSgene (Approved drugs only)

Drug status

DrugBank ID

Name

Type

Drug structure

Gene-centered ligand-gene interaction network

Ligands binding to mutated ligand binding site of EIF2AK3 go to BioLip

Ligand ID	Ligand short name	Ligand long name	PDB ID	PDB name	mutLBS
3Z1		2-AMINO-N-[4-METHOXY-3-(TRIFLUOROMETHYL)PHENYL]-4- METHYL-3-[2-(METHYLAMINO)QUINAZOLIN-6-YL]BENZAMIDE	4x7j	A	K622
3Z2		N-{5-[(6,7-DIMETHOXYQUINOLIN-4-YL)OXY]PYRIDIN-2-YL}-1- METHYL-3-OXO-2-PHENYL-5-(PYRIDIN-4-YL)-2,3-DIHYDRO-1H- PYRAZOLE-4-CARBOXAMIDE	4x7h	A	K622
3Z3		4-{2-AMINO-3-[5-FLUORO-2-(METHYLAMINO)QUINAZOLIN-6-YL]- 4-METHYLBENZOYL}-1-METHYL-2,5-DIPHENYL-1,2-DIHYDRO-3H- PYRAZOL-3-ONE	4x7k	A	K622 I651
3Z4		4-{2-AMINO-4-METHYL-3-[2-(METHYLAMINO)-1,3- BENZOTHIAZOL-6-YL]BENZOYL}-1-METHYL-2,5-DIPHENYL-1,2- DIHYDRO-3H-PYRAZOL-3-ONE	4x7l	A	K622 I651
3Z5		4-[2-AMINO-4-METHYL-3-(2-METHYLQUINOLIN-6-YL)BENZOYL]- 1-METHYL-2,5-DIPHENYL-1,2-DIHYDRO-3H-PYRAZOL-3-ONE	4x7n	A	K622 I651
3Z6		1-[5-(4-AMINO-2,7-DIMETHYL-7H-PYRROLO[2,3-D]PYRIMIDIN- 5-YL)-2,3-DIHYDRO-1H-INDOL-1-YL]-2-[3-FLUORO-5- (TRIFLUOROMETHYL)PHENYL]ETHANONE	4x7o	A	K622 V640 A644

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Conservation information for LBS of EIF2AK3

Multiple alignments for Q9NZJ5 in multiple species

LBS

AA sequence

# species

Species