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 RRM2

Gene summary

Basic gene Info.	Gene symbol	RRM2
	Gene name	ribonucleotide reductase M2
	Synonyms	R2\|RR2\|RR2M
	Cytomap	UCSC genome browser: 2p25-p24
	Type of gene	protein-coding
	RefGenes	NM_001034.3, NM_001165931.1,
	Description	ribonucleoside-diphosphate reductase subunit M2ribonucleotide reductase M2 polypeptideribonucleotide reductase small chainribonucleotide reductase small subunit
	Modification date	20141222
dbXrefs	MIM : 180390
	HGNC : HGNC
	Ensembl : ENSG00000171848
	HPRD : 01587
	Vega : OTTHUMG00000090449
Protein	UniProt: P31350 go to UniProt's Cross Reference DB Table
Expression	CleanEX: HS_RRM2
	BioGPS: 6241
Pathway	NCI Pathway Interaction Database: RRM2
	KEGG: RRM2
	REACTOME: RRM2
	Pathway Commons: RRM2
Context	iHOP: RRM2
	ligand binding site mutation search in PubMed: RRM2
	UCL Cancer Institute: RRM2
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 RRM2

Cancer type specific mutLBS sorted by frequency

LBS	AAchange of nsSNV	Cancer type	# samples
E169	M168V	COAD	1
H269	D271E	COAD	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 RRM2

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
E169	M168V	-1.4418889
H269	D271E	-0.61629242

(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 RRM2 from PDB

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Differential gene expression and gene-gene network for RRM2

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 RRM2 and the right PPI network was created from samples without mutations in the LBS of RRM2. 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 RRM2

Gene level disease information (DisGeNet)

Disease ID	Disease name	# PubMed	Association type
umls:C2239176	Carcinoma, Hepatocellular	4	Biomarker
umls:C0009404	Colorectal Neoplasms	1	Biomarker
umls:C0017661	Glomerulonephritis, IGA	1	Biomarker
umls:C0032460	Polycystic Ovary Syndrome	1	Biomarker

Mutation level pathogenic information (ClinVar annotation)

Allele ID

AA change

Clinical significance

Origin

Phenotype IDs

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Pharmacological information for RRM2

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\|investigational	DB00242	Cladribine	Small molecule
Investigational	DB05003	Imexon	Small molecule
Approved\|investigational	DB05260	Gallium nitrate	Small molecule
Investigational	DB05428	motexafin gadolinium	Small molecule
Investigational	DB05801	GTI 2040	Small molecule

Gene-centered ligand-gene interaction network

Ligands binding to mutated ligand binding site of RRM2 go to BioLip

Ligand ID	Ligand short name	Ligand long name	PDB ID	PDB name	mutLBS
FE		IRON(3+)	2uw2	A	E169 H269
FE		IRON(3+)	3vpm	A	E169 H269
FE		IRON(3+)	3vpm	B	E169 H269
FE		IRON(3+)	3vpn	A	E169 H269
FE		IRON(3+)	3vpn	B	E169 H269
FE		IRON(3+)	3vpo	A	E169 H269
FE		IRON(3+)	3vpo	B	E169 H269

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Conservation information for LBS of RRM2

Multiple alignments for P31350 in multiple species

LBS	AA sequence	# species	Species
E169	FQIAMENIHSE	5	Homo sapiens, Danio rerio, Danio rerio, Mus musculus, Rattus norvegicus
E169	FQIAIENIHSE	2	Caenorhabditis elegans, Arabidopsis thaliana
E169	FQIMIENIHSE	2	Saccharomyces cerevisiae (strain ATCC 204508 / S288c), Schizosaccharomyces pombe (strain 972 / ATCC 24843)
E169	FQIMMENIHSE	1	Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987)
E169	FQIAMENVHSE	1	Drosophila melanogaster
E232	AFAAVEGIFFS	9	Homo sapiens, Caenorhabditis elegans, Schizosaccharomyces pombe (strain 972 / ATCC 24843), Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987), Drosophila melanogaster, Danio rerio, Danio rerio, Mus musculus, Rattus norve
E232	AFASIEGVFFS	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
E232	AFACVEGIFFS	1	Arabidopsis thaliana
E266	LISRDEGLHCD	7	Homo sapiens, Arabidopsis thaliana, Drosophila melanogaster, Danio rerio, Danio rerio, Mus musculus, Rattus norvegicus
E266	LICRDEGLHTD	2	Saccharomyces cerevisiae (strain ATCC 204508 / S288c), Schizosaccharomyces pombe (strain 972 / ATCC 24843)
E266	LISRDEGLHRD	1	Caenorhabditis elegans
E266	LISRDEGLHTD	1	Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987)
H269	RDEGLHCDFAC	6	Homo sapiens, Arabidopsis thaliana, Danio rerio, Danio rerio, Mus musculus, Rattus norvegicus
H269	RDEGLHTDFAC	3	Saccharomyces cerevisiae (strain ATCC 204508 / S288c), Schizosaccharomyces pombe (strain 972 / ATCC 24843), Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987)
H269	RDEGLHRDFAC	1	Caenorhabditis elegans
H269	RDEGLHCDFAV	1	Drosophila melanogaster
R78	LRENPRRFVIF	2	Homo sapiens, Drosophila melanogaster
R78	LKENPHRFVIF	2	Danio rerio, Danio rerio
R78	LRENPRRFVVF	2	Mus musculus, Rattus norvegicus
R78	LQDLDNRFVIF	1	Caenorhabditis elegans
R78	LNEDKERTVLF	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
R78	LRPNPHRFVLF	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
R78	LTENPQRFVLF	1	Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987)
R78	LTPTPDRFCMF	1	Arabidopsis thaliana
T156	QEVQVTEARCF	4	Danio rerio, Danio rerio, Mus musculus, Rattus norvegicus
T156	QEVQITEARCF	2	Homo sapiens, Drosophila melanogaster
T156	NEVQVSEARFF	1	Caenorhabditis elegans
T156	TEVQIPEAKSF	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
T156	SEVQIPEARCV	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
T156	GEVQIPEARCF	1	Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987)
T156	SDVQVSEARAF	1	Arabidopsis thaliana
V141	ASDGIVNENLV	8	Homo sapiens, Saccharomyces cerevisiae (strain ATCC 204508 / S288c), Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987), Drosophila melanogaster, Danio rerio, Danio rerio, Mus musculus, Rattus norvegicus
V141	ASDGIVNENLC	1	Caenorhabditis elegans
V141	ASDGIVNENLL	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
V141	ASDGIVLENLA	1	Arabidopsis thaliana
V81	NPHRFVIFPIQ	2	Danio rerio, Danio rerio
V81	NPRRFVVFPIE	2	Mus musculus, Rattus norvegicus
V81	NPRRFVIFPIE	1	Homo sapiens
V81	LDNRFVIFPLK	1	Caenorhabditis elegans
V81	DKERTVLFPIK	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
V81	NPHRFVLFPIK	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
V81	NPQRFVLFPIK	1	Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987)
V81	TPDRFCMFPIH	1	Arabidopsis thaliana
V81	NPRRFVIFPIQ	1	Drosophila melanogaster