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 RARA

Gene summary

Basic gene Info.	Gene symbol	RARA
	Gene name	retinoic acid receptor, alpha
	Synonyms	NR1B1\|RAR
	Cytomap	UCSC genome browser: 17q21
	Type of gene	protein-coding
	RefGenes	NM_000964.3, NM_001024809.3,NM_001145301.2,NM_001145302.2,NM_001033603.1,
	Description	RAR-alphanuclear receptor subfamily 1 group B member 1nucleophosmin-retinoic acid receptor alpha fusion protein NPM-RAR long formretinoic acid nuclear receptor alpha variant 1retinoic acid nuclear receptor alpha variant 2retinoic acid receptor alpha
	Modification date	20141207
dbXrefs	MIM : 180240
	HGNC : HGNC
	Ensembl : ENSG00000131759
	HPRD : 06769
	Vega : OTTHUMG00000133328
Protein	UniProt: P10276 go to UniProt's Cross Reference DB Table
Expression	CleanEX: HS_RARA
	BioGPS: 5914
Pathway	NCI Pathway Interaction Database: RARA
	KEGG: RARA
	REACTOME: RARA
	Pathway Commons: RARA
Context	iHOP: RARA
	ligand binding site mutation search in PubMed: RARA
	UCL Cancer Institute: RARA
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 RARA.	1. "Marasca R, Zucchini P, Galimberti S, Leonardi G, Vaccari P, Donelli A, Luppi M, Petrini M, Torelli G. Missense mutations in the PML/RARalpha ligand binding domain in ATRA-resistant As(2)O(3) sensitive relapsed acute promyelocytic leukemia. Haematologica. 1999 Nov;84(11):963-8." 10553155 2. "Tan J, Ong CK, Lim WK, Ng CC, Thike AA, Ng LM, Rajasegaran V, Myint SS, Nagarajan S, Thangaraju S, Dey S, Nasir ND, Wijaya GC, Lim JQ, Huang D, Li Z, Wong BH, Chan JY, McPherson JR, Cutcutache I, Poore G, Tay ST, Tan WJ, Putti TC, Ahmad BS, Iau P, Chan CW, Tang AP, Yong WS, Madhukumar P, Ho GH, Tan VK, Wong CY, Hartman M, Ong KW, Tan BK, Rozen SG, Tan P, Tan PH, Teh BT. Genomic landscapes of breast fibroepithelial tumors. Nat Genet. 2015 Nov;47(11):1341-5. doi:10.1038/ng.3409. Epub 2015 Oct 5." 26437033

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

GO ID	GO Term	PubMed ID
GO:0007165	signal transduction	2825025
GO:0030520	intracellular estrogen receptor signaling pathway	15831516
GO:0030853	negative regulation of granulocyte differentiation	19917671
GO:0032355	response to estradiol	15831516
GO:0032689	negative regulation of interferon-gamma production	18416830
GO:0032720	negative regulation of tumor necrosis factor production	18416830
GO:0032736	positive regulation of interleukin-13 production	18416830
GO:0032753	positive regulation of interleukin-4 production	18416830
GO:0032754	positive regulation of interleukin-5 production	18416830
GO:0045630	positive regulation of T-helper 2 cell differentiation	18416830
GO:0045892	negative regulation of transcription, DNA-templated	20080953
GO:0045893	positive regulation of transcription, DNA-templated	18845237
GO:0045944	positive regulation of transcription from RNA polymerase II promoter	19850744
GO:0071300	cellular response to retinoic acid	19917671
GO:0071391	cellular response to estrogen stimulus	20080953

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Ligand binding site mutations for RARA

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
G301	N299S	BLCA	1
F286	F286S	BRCA	1
R272	R272W	COAD	1
L319	P318S	COAD	1
R144	Q146R	KIRC	1
Q216	E215G	KIRC	1
N212	T210A	KIRC	1
F286	M284I	LUAD	1
Q257	D256Y	LUAD	1
C108	C108S	LUSC	1
Q257	D256N	SKCM	1
S213	S214L	SKCM	1
N138	R139S	STAD	1
F302	G303S	STAD	1
S157	S157P	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 RARA

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
C108	C108S	-1.4964716
R272	R272W	-1.3523993
L319	P318S	-1.3037648
N138	R139S	-1.2851222
N212	T210A	-1.2151495
Q257	D256N	-1.1698831
R144	Q146R	-1.1389266
F286	M284I	-1.0852297
F286	F286S	-1.0789413
Q216	E215G	-0.94231742
Q257	D256Y	-0.83993369
G301	N299S	-0.80163256
S157	S157P	-0.74799753
F302	G303S	-0.063832314
S213	S214L	-0.050812043

(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 RARA from PDB

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Differential gene expression and gene-gene network for RARA

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

Gene level disease information (DisGeNet)

Disease ID	Disease name	# PubMed	Association type
umls:C0023487	Leukemia, Promyelocytic, Acute	372	AlteredExpression, Biomarker, GeneticVariation
umls:C2239176	Carcinoma, Hepatocellular	5	Biomarker
umls:C0085183	Neoplasms, Second Primary	1	Biomarker
umls:C0149940	Sciatic Neuropathy	1	Biomarker

Mutation level pathogenic information (ClinVar annotation)

Allele ID

AA change

Clinical significance

Origin

Phenotype IDs

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Pharmacological information for RARA

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	DB00210	Adapalene	Small molecule
Approved	DB00459	Acitretin	Small molecule
Approved\|investigational	DB00523	Alitretinoin	Small molecule
Approved\|investigational	DB00799	Tazarotene	Small molecule
Withdrawn	DB00926	Etretinate	Small molecule
Approved	DB00982	Isotretinoin	Small molecule
Approved\|investigational	DB04942	Tamibarotene	Small molecule
Investigational	DB05785	LGD-1550	Small molecule

Gene-centered ligand-gene interaction network

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

Ligand ID	Ligand short name	Ligand long name	PDB ID	PDB name	mutLBS
REA		RETINOIC ACID	3a9e	B	F286
BMS		4-[(4,4-DIMETHYL-1,2,3,4-TETRAHYDRO-[1,2']BINAPTHALENYL-7-CARBONYL)-AMINO]-BENZOIC ACID	1dkf	B	F286 F302
EQN		4-{[(5,5,8,8-TETRAMETHYL-5,6,7,8-TETRAHYDRONAPHTHALEN-2-YL)CARBONYL]AMINO}BENZOIC ACID	3kmr	A	F286 F302
EQO		4-{(E)-2-[5,5-DIMETHYL-8-(PHENYLETHYNYL)-5,6-DIHYDRONAPHTHALEN-2-YL]ETHENYL}BENZOIC ACID	3kmz	B	F286 F302
EQO		4-{(E)-2-[5,5-DIMETHYL-8-(PHENYLETHYNYL)-5,6-DIHYDRONAPHTHALEN-2-YL]ETHENYL}BENZOIC ACID	3kmz	A	F286 F302
LUF	LUFFARIELLOLIDE	(5S)-4-[(3E,7E)-4,8-DIMETHYL-10-(2,6,6- TRIMETHYLCYCLOHEX-1-EN-1-YL)DECA-3,7-DIEN-1-YL]-5- HYDROXYFURAN-2(5H)-ONE	4dqm	C	F286 F302
III		Peptide ligand (ARG,LEU,ILE,THR,LEU,ALA,ASP,HIS,ILE,CYS,GLN,ILE,ILE,THR,GLN,ASP,PHE,ALA,ARG)	3kmz	B	N212 S213
III		Peptide ligand (ARG,LEU,ILE,THR,LEU,ALA,ASP,HIS,ILE,CYS,GLN,ILE,ILE,THR,GLN,ASP,PHE,ALA,ARG)	3kmz	A	N212 S213 Q216
III		Peptide ligand (LYS,HIS,LYS,ILE,LEU,HIS,ARG,LEU,LEU,GLN,ASP)	3a9e	B	Q257
III		Peptide ligand (HIS,LYS,ILE,LEU,HIS,ARG,LEU,LEU,GLN,GLU)	3kmr	A	Q257
III		Peptide ligand (ARG,LEU,ILE,THR,LEU,ALA,ASP,HIS,ILE,CYS,GLN,ILE,ILE,THR,GLN,ASP,PHE,ALA,ARG)	3kmz	B	Q257
III		Peptide ligand (ARG,LEU,ILE,THR,LEU,ALA,ASP,HIS,ILE,CYS,GLN,ILE,ILE,THR,GLN,ASP,PHE,ALA,ARG)	3kmz	A	Q257
III		Peptide ligand (LYS,SER,LEU,LEU,GLN,GLN,LEU,LEU,THR,GLU)	4dqm	A	Q257
III		Peptide ligand (LYS,SER,LEU,LEU,GLN,GLN,LEU,LEU,THR,GLU)	4dqm	C	Q257
LUF	LUFFARIELLOLIDE	(5S)-4-[(3E,7E)-4,8-DIMETHYL-10-(2,6,6- TRIMETHYLCYCLOHEX-1-EN-1-YL)DECA-3,7-DIEN-1-YL]-5- HYDROXYFURAN-2(5H)-ONE	4dqm	A	R272 F286 G301 F302

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Conservation information for LBS of RARA

Multiple alignments for P10276 in multiple species

LBS	AA sequence	# species	Species
A392	ISAKGAERVIT	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
C105	YGVSACEGCKG	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
C108	SACEGCKGFFR	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
C235	ELSTKCIIKTV	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
C265	LLKAACLDILI	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
C88	RIYKPCFVCQD	5	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio
C88	RVYKPCFVCQD	1	Danio rerio
C91	KPCFVCQDKSS	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
D221	QRVSLDIDLWD	4	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus
D221	RRVALDVDLWD	1	Danio rerio
D221	HRVALDVDLWD	1	Danio rerio
E106	GVSACEGCKGF	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
E412	PPLIQEMLENS	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
F199	AHQETFPALCQ	4	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus
F199	AHQETFPSLCQ	2	Danio rerio, Danio rerio
F228	DLWDKFSELST	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
F286	QDTMTFSDGLT	5	Homo sapiens, Gallus gallus, Mus musculus, Danio rerio, Danio rerio
F286	QDTMTFSEGLT	1	Canis lupus familiaris
F302	MHNAGFGPLTD	5	Homo sapiens, Gallus gallus, Mus musculus, Danio rerio, Danio rerio
F302	MHKAGFGPLTD	1	Canis lupus familiaris
G107	VSACEGCKGFF	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
G301	QMHNAGFGPLT	5	Homo sapiens, Gallus gallus, Mus musculus, Danio rerio, Danio rerio
G301	QMHKAGFGPLT	1	Canis lupus familiaris
G391	SISAKGAERVI	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
H99	KSSGYHYGVSA	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
I236	LSTKCIIKTVE	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
I237	STKCIIKTVEF	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
I254	FTTLTIADQIT	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
I258	TIADQITLLKA	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
I270	CLDILILRICT	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
I273	ILILRICTRYT	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
I396	GAERVITLKME	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
K109	ACEGCKGFFRR	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
K244	TVEFAKQLPGF	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
K262	QITLLKAACLD	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
K399	RVITLKMEIPG	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
L231	DKFSELSTKCI	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
L261	DQITLLKAACL	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
L266	LKAACLDILIL	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
L269	ACLDILILRIC	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
L319	NQLLPLEMDDA	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
L398	ERVITLKMEIP	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
L409	GSMPPLIQEML	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
M400	VITLKMEIPGS	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
M406	EIPGSMPPLIQ	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
M413	PLIQEMLENSE	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
N138	NKVTRNRCQYC	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
N212	KYTTNNSSEQR	4	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus
N212	KYTTSNSSERR	1	Danio rerio
N212	KYTTNNSADHR	1	Danio rerio
P408	PGSMPPLIQEM	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
Q117	FRRSIQKNMVY	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
Q141	TRNRCQYCRLQ	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
Q216	NNSSEQRVSLD	4	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus
Q216	SNSSERRVALD	1	Danio rerio
Q216	NNSADHRVALD	1	Danio rerio
Q257	LTIADQITLLK	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
R113	CKGFFRRSIQK	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
R114	KGFFRRSIQKN	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
R137	INKVTRNRCQY	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
R144	RCQYCRLQKCF	4	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus
R144	RCQYCRLQKCL	2	Danio rerio, Danio rerio
R159	SKESVRNDRNK	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
R272	DILILRICTRY	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
R276	LRICTRYTPEQ	5	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio
R276	LRICTRYTPDQ	1	Danio rerio
R394	AKGAERVITLK	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
S157	GMSKESVRNDR	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
S213	YTTNNSSEQRV	4	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus
S213	YTTSNSSERRV	1	Danio rerio
S213	YTTNNSADHRV	1	Danio rerio
S229	LWDKFSELSTK	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
S232	KFSELSTKCII	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
S287	DTMTFSDGLTL	5	Homo sapiens, Gallus gallus, Mus musculus, Danio rerio, Danio rerio
S287	DTMTFSEGLTL	1	Canis lupus familiaris
T233	FSELSTKCIIK	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
T397	AERVITLKMEI	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
V158	MSKESVRNDRN	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
V218	SSEQRVSLDID	4	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus
V218	SSERRVALDVD	1	Danio rerio
V218	SADHRVALDVD	1	Danio rerio
V240	CIIKTVEFAKQ	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
V395	KGAERVITLKM	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
W225	LDIDLWDKFSE	4	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus
W225	LDVDLWDKFSE	2	Danio rerio, Danio rerio
Y100	SSGYHYGVSAC	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio
Y98	DKSSGYHYGVS	6	Homo sapiens, Gallus gallus, Canis lupus familiaris, Mus musculus, Danio rerio, Danio rerio