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 NR1H3

Gene summary

Basic gene Info.	Gene symbol	NR1H3
	Gene name	nuclear receptor subfamily 1, group H, member 3
	Synonyms	LXR-a\|LXRA\|RLD-1
	Cytomap	UCSC genome browser: 11p11.2
	Type of gene	protein-coding
	RefGenes	NM_001130101.2, NM_001130102.2,NM_001251934.1,NM_001251935.1,NM_005693.3,
	Description	liver X nuclear receptor alpha variant 1oxysterols receptor LXR-alpha
	Modification date	20141222
dbXrefs	MIM : 602423
	HGNC : HGNC
	Ensembl : ENSG00000025434
	HPRD : 07211
	Vega : OTTHUMG00000150628
Protein	UniProt: Q13133 go to UniProt's Cross Reference DB Table
Expression	CleanEX: HS_NR1H3
	BioGPS: 10062
Pathway	NCI Pathway Interaction Database: NR1H3
	KEGG: NR1H3
	REACTOME: NR1H3
	Pathway Commons: NR1H3
Context	iHOP: NR1H3
	ligand binding site mutation search in PubMed: NR1H3
	UCL Cancer Institute: NR1H3
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:0010870	positive regulation of receptor biosynthetic process	18511497
GO:0010875	positive regulation of cholesterol efflux	16141411
GO:0032376	positive regulation of cholesterol transport	16141411
GO:0032570	response to progesterone	16141411
GO:0034145	positive regulation of toll-like receptor 4 signaling pathway	18511497
GO:0045944	positive regulation of transcription from RNA polymerase II promoter	16141411
GO:0071222	cellular response to lipopolysaccharide	18511497
GO:2000189	positive regulation of cholesterol homeostasis	18511497

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Ligand binding site mutations for NR1H3

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
N225	R226W	COAD	3
F254	R253H	COAD	2
I295	A294V	COAD	1
N225	Q223L	LUAD	1
N225	R227L	LUAD	1
N225	R226Q	OV	1
R283	R283P	SKCM	1
I313,F315	T314I	SKCM	1
N225	R227H	STAD	1
R232	R234Q	UCEC	1
R232	R232Q	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 NR1H3

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
N225	R227H	-1.6344547
R232	R232Q	-1.2751175
R232	R234Q	-1.272859
N225	R227L	-0.95243027
N225	R226Q	-0.87532468
F254	R253H	-0.85721248
R283	R283P	-0.57781313
N225	R226W	-0.54110446
I295	A294V	-0.32887438
I313	T314I	-0.24817607
F315	T314I	-0.24817607
N225	Q223L	-0.13619305

(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 NR1H3 from PDB

PDB ID	PDB title	PDB structure
1UHL	Crystal structure of the LXRalfa-RXRbeta LBD heterodimer

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Differential gene expression and gene-gene network for NR1H3

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 NR1H3 and the right PPI network was created from samples without mutations in the LBS of NR1H3. 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 NR1H3

Gene level disease information (DisGeNet)

Disease ID	Disease name	# PubMed	Association type
umls:C0015695	Fatty Liver	3	Biomarker
umls:C0008370	Cholestasis	1	Therapeutic
umls:C0860207	Drug-Induced Liver Injury	1	Therapeutic

Mutation level pathogenic information (ClinVar annotation)

Allele ID

AA change

Clinical significance

Origin

Phenotype IDs

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Pharmacological information for NR1H3

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	DB07080	N-(2,2,2-TRIFLUOROETHYL)-N-{4-[2,2,2-TRIFLUORO-1-HYDROXY-1-(TRIFLUOROMETHYL)ETHYL]PHENYL}BENZENESULFONAMIDE	Small molecule
Experimental	DB07929	N-(TERT-BUTYL)-3,5-DIMETHYL-N'-[(5-METHYL-2,3-DIHYDRO-1,4-BENZODIOXIN-6-YL)CARBONYL]BENZOHYDRAZIDE	Small molecule
Experimental	DB08063	1-BENZYL-3-(4-METHOXYPHENYLAMINO)-4-PHENYLPYRROLE-2,5-DIONE	Small molecule
Experimental	DB08175	(2E,4E)-11-METHOXY-3,7,11-TRIMETHYLDODECA-2,4-DIENOIC ACID	Small molecule

Gene-centered ligand-gene interaction network

Ligands binding to mutated ligand binding site of NR1H3 go to BioLip

Ligand ID	Ligand short name	Ligand long name	PDB ID	PDB name	mutLBS
4KQ		2-[4-[4-[[2-[(2-METHYLPROPAN-2-YL)OXYCARBONYL]-3- OXIDANYL-4-(TRIFLUOROMETHYL) PHENYL]METHOXY]PHENYL]PHENYL]ETHANOIC ACID	5avl	A	F254 I295 F315
O90		{3-CHLORO-4-[(3-{[7-PROPYL-3-(TRIFLUOROMETHYL)-1,2-BENZISOXAZOL-6-YL]OXY}PROPYL)SULFANYL]PHENYL}ACETICACID	3ips	A	F315
O90		{3-CHLORO-4-[(3-{[7-PROPYL-3-(TRIFLUOROMETHYL)-1,2-BENZISOXAZOL-6-YL]OXY}PROPYL)SULFANYL]PHENYL}ACETICACID	3ips	B	F315
4KM		TERT-BUTYL 2-[[4-[ETHANOYL(METHYL) AMINO]PHENOXY]METHYL]-5-(TRIFLUOROMETHYL)BENZOATE	5avi	A	I295 F315
4KM		TERT-BUTYL 2-[[4-[ETHANOYL(METHYL) AMINO]PHENOXY]METHYL]-5-(TRIFLUOROMETHYL)BENZOATE	5avi	C	I295 F315
965		[3-(3-{[2-CHLORO-3-(TRIFLUOROMETHYL)BENZYL](2,2-DIPHENYLETHYL)AMINO}PROPOXY)PHENYL]ACETIC ACID	3ipq	A	I295 I313 F315
O40		4-{[METHYL(3-{[7-PROPYL-3-(TRIFLUOROMETHYL)-1,2-BENZISOXAZOL-6-YL]OXY}PROPYL)CARBAMOYL]AMINO}BENZOICACID	3ipu	A	N225 R232 I295 F315
O40		4-{[METHYL(3-{[7-PROPYL-3-(TRIFLUOROMETHYL)-1,2-BENZISOXAZOL-6-YL]OXY}PROPYL)CARBAMOYL]AMINO}BENZOICACID	3ipu	B	N225 R232 I295 F315
III		Peptide ligand (HIS,LYS,ILE,LEU,HIS,ARG,LEU,LEU,GLN,ASP)	1uhl	B	R283
III		Peptide ligand (SER,LEU,THR,GLU,ARG,HIS,LYS,ILE,LEU,HIS,ARG,LEU,LEU,GLN,GLU)	3ipq	A	R283
III		Peptide ligand (SER,LEU,THR,GLU,ARG,HIS,LYS,ILE,LEU,HIS,ARG,LEU,LEU,GLN,GLU)	3ips	B	R283
III		Peptide ligand (SER,LEU,THR,GLU,ARG,HIS,LYS,ILE,LEU,HIS,ARG,LEU,LEU,GLN,GLU)	3ipu	A	R283
III		Peptide ligand (SER,LEU,THR,GLU,ARG,HIS,LYS,ILE,LEU,HIS,ARG,LEU,LEU,GLN,GLU)	3ipu	B	R283
III		Peptide ligand (SER,LEU,THR,GLU,ARG,HIS,LYS,ILE,LEU,HIS,ARG,LEU,LEU,GLN,GLU)	5avi	A	R283
III		Peptide ligand (SER,LEU,THR,GLU,ARG,HIS,LYS,ILE,LEU,HIS,ARG,LEU,LEU,GLN,GLU)	5avi	C	R283
III		Peptide ligand (SER,LEU,THR,GLU,ARG,HIS,LYS,ILE,LEU,HIS,ARG,LEU,LEU,GLN,GLU)	5avl	A	R283

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Conservation information for LBS of NR1H3

Multiple alignments for Q13133 in multiple species

LBS	AA sequence	# species	Species
A261	HFTELAIVSVQ	3	Homo sapiens, Mus musculus, Bos taurus
A288	REDQIALLKTS	3	Homo sapiens, Mus musculus, Bos taurus
E284	LQLSREDQIAL	3	Homo sapiens, Mus musculus, Bos taurus
E301	EVMLLETSRRY	3	Homo sapiens, Mus musculus, Bos taurus
E441	PPLLSEIWDVH	3	Homo sapiens, Mus musculus, Bos taurus
F254	ARQQRFAHFTE	3	Homo sapiens, Mus musculus, Bos taurus
F257	QRFAHFTELAI	3	Homo sapiens, Mus musculus, Bos taurus
F278	KQLPGFLQLSR	3	Homo sapiens, Mus musculus, Bos taurus
F315	SESITFLKDFS	3	Homo sapiens, Mus musculus, Bos taurus
F326	YNREDFAKAGL	3	Homo sapiens, Mus musculus, Bos taurus
F335	GLQVEFINPIF	3	Homo sapiens, Mus musculus, Bos taurus
F340	FINPIFEFSRA	3	Homo sapiens, Mus musculus, Bos taurus
H421	TLSSVHSEQVF	3	Homo sapiens, Mus musculus, Bos taurus
I287	SREDQIALLKT	3	Homo sapiens, Mus musculus, Bos taurus
I295	LKTSAIEVMLL	3	Homo sapiens, Mus musculus, Bos taurus
I313	PGSESITFLKD	3	Homo sapiens, Mus musculus, Bos taurus
I336	LQVEFINPIFE	3	Homo sapiens, Mus musculus, Bos taurus
I339	EFINPIFEFSR	3	Homo sapiens, Mus musculus, Bos taurus
K273	IVDFAKQLPGF	3	Homo sapiens, Mus musculus, Bos taurus
K291	QIALLKTSAIE	3	Homo sapiens, Mus musculus, Bos taurus
L260	AHFTELAIVSV	3	Homo sapiens, Mus musculus, Bos taurus
L290	DQIALLKTSAI	3	Homo sapiens, Mus musculus, Bos taurus
L299	AIEVMLLETSR	3	Homo sapiens, Mus musculus, Bos taurus
L316	ESITFLKDFSY	3	Homo sapiens, Mus musculus, Bos taurus
L331	FAKAGLQVEFI	3	Homo sapiens, Mus musculus, Bos taurus
L428	EQVFALRLQDK	3	Homo sapiens, Mus musculus, Bos taurus
L435	LQDKKLPPLLS	3	Homo sapiens, Mus musculus, Bos taurus
L438	KKLPPLLSEIW	3	Homo sapiens, Mus musculus, Bos taurus
L439	KLPPLLSEIWD	3	Homo sapiens, Mus musculus, Bos taurus
M298	SAIEVMLLETS	3	Homo sapiens, Mus musculus, Bos taurus
N225	AQQQCNRRSFS	2	Homo sapiens, Mus musculus
N225	AQQLCNRRSFS	1	Bos taurus
N371	SADRPNVQDQL	3	Homo sapiens, Mus musculus, Bos taurus
P437	DKKLPPLLSEI	3	Homo sapiens, Mus musculus, Bos taurus
Q266	AIVSVQEIVDF	3	Homo sapiens, Mus musculus, Bos taurus
Q286	LSREDQIALLK	3	Homo sapiens, Mus musculus, Bos taurus
Q424	SVHSEQVFALR	3	Homo sapiens, Mus musculus, Bos taurus
R232	RSFSDRLRVTP	2	Homo sapiens, Mus musculus
R232	RSFSDQLRVTP	1	Bos taurus
R283	FLQLSREDQIA	3	Homo sapiens, Mus musculus, Bos taurus
R305	LETSRRYNPGS	3	Homo sapiens, Mus musculus, Bos taurus
S264	ELAIVSVQEIV	3	Homo sapiens, Mus musculus, Bos taurus
T258	RFAHFTELAIV	3	Homo sapiens, Mus musculus, Bos taurus
T302	VMLLETSRRYN	3	Homo sapiens, Mus musculus, Bos taurus
V269	SVQEIVDFAKQ	3	Homo sapiens, Mus musculus, Bos taurus
W443	LLSEIWDVHE	3	Homo sapiens, Mus musculus, Bos taurus