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 MTOR

Gene summary

Basic gene Info.	Gene symbol	MTOR
	Gene name	mechanistic target of rapamycin (serine/threonine kinase)
	Synonyms	FRAP\|FRAP1\|FRAP2\|RAFT1\|RAPT1
	Cytomap	UCSC genome browser: 1p36.2
	Type of gene	protein-coding
	RefGenes	NM_004958.3,
	Description	FK506 binding protein 12-rapamycin associated protein 2FK506-binding protein 12-rapamycin complex-associated protein 1FKBP-rapamycin associated proteinFKBP12-rapamycin complex-associated protein 1mammalian target of rapamycinrapamycin and FKBP12 targ
	Modification date	20141222
dbXrefs	MIM : 601231
	HGNC : HGNC
	Ensembl : ENSG00000198793
	HPRD : 03134
	Vega : OTTHUMG00000002001
Protein	UniProt: P42345 go to UniProt's Cross Reference DB Table
Expression	CleanEX: HS_MTOR
	BioGPS: 2475
Pathway	NCI Pathway Interaction Database: MTOR
	KEGG: MTOR
	REACTOME: MTOR
	Pathway Commons: MTOR
Context	iHOP: MTOR
	ligand binding site mutation search in PubMed: MTOR
	UCL Cancer Institute: MTOR
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 MTOR.	1. Rodrik-Outmezguine, V. S., Okaniwa, M., Yao, Z., Novotny, C. J., McWhirter, C., Banaji, A., ... & Barratt, D. G. (2016). Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor. Nature. 27279227

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

GO ID	GO Term	PubMed ID
GO:0001934	positive regulation of protein phosphorylation	20233713
GO:0006468	protein phosphorylation	15467718
GO:0016049	cell growth	18762023
GO:0016310	phosphorylation	11853878
GO:0043200	response to amino acid	18497260
GO:0045727	positive regulation of translation	18762023
GO:0046777	protein autophosphorylation	15467718

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Ligand binding site mutations for MTOR

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
W2101	W2101L	BRCA	1
Y2225	Q2223K	COAD	1
E2032	E2033V	KIRC	1
Y2225	A2226S	LUAD	1
D2195	R2193C	STAD	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 MTOR

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
Y2225	A2226S	-1.2879841
D2195	R2193C	-0.80400537
E2032	E2033V	-0.69240274
Y2225	Q2223K	-0.68486235
W2101	W2101L	-0.43835689

(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 MTOR from PDB

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Differential gene expression and gene-gene network for MTOR

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

Gene level disease information (DisGeNet)

Disease ID	Disease name	# PubMed	Association type
umls:C0007134	Carcinoma, Renal Cell	25	Biomarker
umls:C2239176	Carcinoma, Hepatocellular	19	Biomarker
umls:C0334634	Lymphoma, Mantle-Cell	7	Biomarker
umls:C0001418	Adenocarcinoma	4	AlteredExpression, Biomarker
umls:C1961099	Precursor T-Cell Lymphoblastic Leukemia-Lymphoma	4	Biomarker
umls:C0919267	Ovarian Neoplasms	3	AlteredExpression, Biomarker
umls:C0149721	Hypertrophy, Left Ventricular	2	Biomarker
umls:C0025500	Mesothelioma	2	AlteredExpression, Biomarker
umls:C1955869	Malformations of Cortical Development	2	Biomarker
umls:C0262584	Carcinoma, Small Cell	1	Biomarker
umls:C0020538	Hypertension	1	Biomarker
umls:C0235032	Neurotoxicity Syndromes	1	Biomarker
umls:C0036341	Schizophrenia	1	Biomarker
umls:C0007873	Uterine Cervical Neoplasms	1	Biomarker

Mutation level pathogenic information (ClinVar annotation)

Allele ID

AA change

Clinical significance

Origin

Phenotype IDs

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Pharmacological information for MTOR

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	DB00337	Pimecrolimus	Small molecule
Approved\|investigational	DB00877	Sirolimus	Small molecule
Approved	DB01590	Everolimus	Small molecule
Investigational	DB04974	AP1903	Small molecule
Investigational	DB05210	SF1126	Small molecule
Investigational	DB05241	XL765	Small molecule
Approved	DB06287	Temsirolimus	Small molecule

Gene-centered ligand-gene interaction network

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

Ligand ID	Ligand short name	Ligand long name	PDB ID	PDB name	mutLBS
P2X		2-[4-AMINO-1-(PROPAN-2-YL)-1H-PYRAZOLO[3,4-D]PYRIMIDIN- 3-YL]-1H-INDOL-5-OL	4jt5	B	D2195 Y2225
P2X		2-[4-AMINO-1-(PROPAN-2-YL)-1H-PYRAZOLO[3,4-D]PYRIMIDIN- 3-YL]-1H-INDOL-5-OL	4jt5	A	D2195 Y2225
X6K		PI-103	4jt6	B	D2195 Y2225
X6K		PI-103	4jt6	A	D2195 Y2225
RAP		RAPAMYCIN IMMUNOSUPPRESSANT DRUG	4drj	B	E2032 W2101
RAP		RAPAMYCIN IMMUNOSUPPRESSANT DRUG	5flc	F	E2032 W2101
RAP		RAPAMYCIN IMMUNOSUPPRESSANT DRUG	1fap	B	W2101
RAP		RAPAMYCIN IMMUNOSUPPRESSANT DRUG	4drh	B	W2101
RAP		RAPAMYCIN IMMUNOSUPPRESSANT DRUG	4drh	E	W2101
RAP		RAPAMYCIN IMMUNOSUPPRESSANT DRUG	4dri	B	W2101
AGS		ADENOSINE 5'-[GAMMA-THIO]TRIPHOSPHATE	4jsp	B	Y2225
AGS		ADENOSINE 5'-[GAMMA-THIO]TRIPHOSPHATE	4jsp	A	Y2225

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Conservation information for LBS of MTOR

Multiple alignments for P42345 in multiple species

LBS	AA sequence	# species	Species
C2243	GWVPHCDTLHA	3	Homo sapiens, Mus musculus, Rattus norvegicus
C2243	GWVPNCDTLHH	1	Arabidopsis thaliana
C2243	GWVPNCDTLHA	1	Oryza sativa subsp. japonica
C2243	GWVPNSDTFHV	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
C2243	GWVLDSDTLHV	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
D2102	LTQAWDLYYHV	4	Homo sapiens, Arabidopsis thaliana, Mus musculus, Rattus norvegicus
D2102	LTKAWDLYYHV	1	Oryza sativa subsp. japonica
D2102	LNQAWDIYYNV	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
D2102	LNQAWDLYYQV	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
D2195	EDLRQDERVMQ	5	Homo sapiens, Arabidopsis thaliana, Oryza sativa subsp. japonica, Mus musculus, Rattus norvegicus
D2195	EDIRQDSLVMQ	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
D2195	EDIRQDERVMQ	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
D2338	ILGLGDRHPSN	6	Homo sapiens, Arabidopsis thaliana, Mus musculus, Rattus norvegicus, Saccharomyces cerevisiae (strain ATCC 204508 / S288c), Schizosaccharomyces pombe (strain 972 / ATCC 24843)
D2338	LLGLGDRHPSN	1	Oryza sativa subsp. japonica
D2357	KILHIDFGDCF	5	Homo sapiens, Arabidopsis thaliana, Oryza sativa subsp. japonica, Mus musculus, Rattus norvegicus
D2357	KVIHIDFGDCF	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
D2357	NIIHIDFGDCF	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
E2032	WHEGLEEASRL	4	Homo sapiens, Mus musculus, Rattus norvegicus, Schizosaccharomyces pombe (strain 972 / ATCC 24843)
E2032	WHEALEEASRL	1	Arabidopsis thaliana
E2032	WHEALEEASRM	1	Oryza sativa subsp. japonica
E2032	WYEGLDDASRQ	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
E2190	LLKGHEDLRQD	5	Homo sapiens, Arabidopsis thaliana, Oryza sativa subsp. japonica, Mus musculus, Rattus norvegicus
E2190	VLKGHEDIRQD	2	Saccharomyces cerevisiae (strain ATCC 204508 / S288c), Schizosaccharomyces pombe (strain 972 / ATCC 24843)
F2039	ASRLYFGERNV	3	Homo sapiens, Mus musculus, Rattus norvegicus
F2039	ASRLYFGEHNI	1	Arabidopsis thaliana
F2039	ASRMYFGEHNI	1	Oryza sativa subsp. japonica
F2039	ASRQFFGEHNT	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
F2039	ASRLYFGDHNI	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
F2108	LYYHVFRRISK	3	Homo sapiens, Mus musculus, Rattus norvegicus
F2108	LYYHVFKRIDK	1	Arabidopsis thaliana
F2108	LYYHVFRRIDK	1	Oryza sativa subsp. japonica
F2108	IYYNVFRKIGK	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
F2108	LYYQVFKKIRK	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
F2358	ILHIDFGDCFE	5	Homo sapiens, Arabidopsis thaliana, Oryza sativa subsp. japonica, Mus musculus, Rattus norvegicus
F2358	VIHIDFGDCFE	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
F2358	IIHIDFGDCFE	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
G2040	SRLYFGERNVK	3	Homo sapiens, Mus musculus, Rattus norvegicus
G2040	SRLYFGEHNIE	1	Arabidopsis thaliana
G2040	SRMYFGEHNIE	1	Oryza sativa subsp. japonica
G2040	SRQFFGEHNTE	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
G2040	SRLYFGDHNIE	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
G2238	NSGLIGWVPHC	3	Homo sapiens, Mus musculus, Rattus norvegicus
G2238	NSGLIGWVPNC	2	Arabidopsis thaliana, Oryza sativa subsp. japonica
G2238	KSGLLGWVPNS	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
G2238	DSGLLGWVLDS	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
H2340	GLGDRHPSNLM	7	Homo sapiens, Arabidopsis thaliana, Oryza sativa subsp. japonica, Mus musculus, Rattus norvegicus, Saccharomyces cerevisiae (strain ATCC 204508 / S288c), Schizosaccharomyces pombe (strain 972 / ATCC 24843)
I2163	PSLQVITSKQR	3	Homo sapiens, Mus musculus, Rattus norvegicus
I2163	RQLVVITSKQR	1	Arabidopsis thaliana
I2163	PQLIVITSKQR	1	Oryza sativa subsp. japonica
I2163	PVFSVISSKQR	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
I2163	PTFNVITSKQR	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
I2237	TNSGLIGWVPH	3	Homo sapiens, Mus musculus, Rattus norvegicus
I2237	PNSGLIGWVPN	2	Arabidopsis thaliana, Oryza sativa subsp. japonica
I2237	PKSGLLGWVPN	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
I2237	PDSGLLGWVLD	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
I2356	GKILHIDFGDC	5	Homo sapiens, Arabidopsis thaliana, Oryza sativa subsp. japonica, Mus musculus, Rattus norvegicus
I2356	GKVIHIDFGDC	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
I2356	GNIIHIDFGDC	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
K2187	FVFLLKGHEDL	3	Homo sapiens, Mus musculus, Rattus norvegicus
K2187	YAFLLKGHEDL	2	Arabidopsis thaliana, Oryza sativa subsp. japonica
K2187	YKYVLKGHEDI	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
K2187	YQYVLKGHEDI	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
L2031	MWHEGLEEASR	3	Homo sapiens, Mus musculus, Rattus norvegicus
L2031	MWHEALEEASR	2	Arabidopsis thaliana, Oryza sativa subsp. japonica
L2031	QWYEGLDDASR	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
L2031	QWHEGLEEASR	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
L2185	HEFVFLLKGHE	3	Homo sapiens, Mus musculus, Rattus norvegicus
L2185	EDYAFLLKGHE	1	Arabidopsis thaliana
L2185	NDYAFLLKGHE	1	Oryza sativa subsp. japonica
L2185	KDYKYVLKGHE	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
L2185	KDYQYVLKGHE	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
M2345	HPSNLMLDRLS	3	Homo sapiens, Mus musculus, Rattus norvegicus
M2345	HPSNLMLHRYS	1	Arabidopsis thaliana
M2345	HPSNLMLDRYS	1	Oryza sativa subsp. japonica
M2345	HPSNLMLDRIT	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
M2345	HPSNLMLDRYT	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
N2343	DRHPSNLMLDR	6	Homo sapiens, Oryza sativa subsp. japonica, Mus musculus, Rattus norvegicus, Saccharomyces cerevisiae (strain ATCC 204508 / S288c), Schizosaccharomyces pombe (strain 972 / ATCC 24843)
N2343	DRHPSNLMLHR	1	Arabidopsis thaliana
Q2167	VITSKQRPRKL	5	Homo sapiens, Arabidopsis thaliana, Oryza sativa subsp. japonica, Mus musculus, Rattus norvegicus
Q2167	VISSKQRPRKF	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
Q2167	VITSKQRPRRL	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
R2036	LEEASRLYFGE	4	Homo sapiens, Arabidopsis thaliana, Mus musculus, Rattus norvegicus
R2036	LEEASRMYFGE	1	Oryza sativa subsp. japonica
R2036	LDDASRQFFGE	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
R2036	LEEASRLYFGD	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
S2035	GLEEASRLYFG	4	Homo sapiens, Mus musculus, Rattus norvegicus, Schizosaccharomyces pombe (strain 972 / ATCC 24843)
S2035	ALEEASRLYFG	1	Arabidopsis thaliana
S2035	ALEEASRMYFG	1	Oryza sativa subsp. japonica
S2035	GLDDASRQFFG	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
S2165	LQVITSKQRPR	3	Homo sapiens, Mus musculus, Rattus norvegicus
S2165	LVVITSKQRPR	1	Arabidopsis thaliana
S2165	LIVITSKQRPR	1	Oryza sativa subsp. japonica
S2165	FSVISSKQRPR	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
S2165	FNVITSKQRPR	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
S2342	GDRHPSNLMLD	6	Homo sapiens, Oryza sativa subsp. japonica, Mus musculus, Rattus norvegicus, Saccharomyces cerevisiae (strain ATCC 204508 / S288c), Schizosaccharomyces pombe (strain 972 / ATCC 24843)
S2342	GDRHPSNLMLH	1	Arabidopsis thaliana
T2098	NVKDLTQAWDL	3	Homo sapiens, Mus musculus, Rattus norvegicus
T2098	KDAELTQAWDL	1	Arabidopsis thaliana
T2098	EDAELTKAWDL	1	Oryza sativa subsp. japonica
T2098	DVSNLNQAWDI	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
T2098	DISDLNQAWDL	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
T2245	VPHCDTLHALI	3	Homo sapiens, Mus musculus, Rattus norvegicus
T2245	VPNCDTLHHLI	1	Arabidopsis thaliana
T2245	VPNCDTLHALI	1	Oryza sativa subsp. japonica
T2245	VPNSDTFHVLI	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
T2245	VLDSDTLHVLI	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
V2240	GLIGWVPHCDT	3	Homo sapiens, Mus musculus, Rattus norvegicus
V2240	GLIGWVPNCDT	2	Arabidopsis thaliana, Oryza sativa subsp. japonica
V2240	GLLGWVPNSDT	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
V2240	GLLGWVLDSDT	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
W2101	DLTQAWDLYYH	3	Homo sapiens, Mus musculus, Rattus norvegicus
W2101	ELTQAWDLYYH	1	Arabidopsis thaliana
W2101	ELTKAWDLYYH	1	Oryza sativa subsp. japonica
W2101	NLNQAWDIYYN	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
W2101	DLNQAWDLYYQ	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
W2239	SGLIGWVPHCD	3	Homo sapiens, Mus musculus, Rattus norvegicus
W2239	SGLIGWVPNCD	2	Arabidopsis thaliana, Oryza sativa subsp. japonica
W2239	SGLLGWVPNSD	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
W2239	SGLLGWVLDSD	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
Y2105	AWDLYYHVFRR	4	Homo sapiens, Oryza sativa subsp. japonica, Mus musculus, Rattus norvegicus
Y2105	AWDLYYHVFKR	1	Arabidopsis thaliana
Y2105	AWDIYYNVFRK	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
Y2105	AWDLYYQVFKK	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
Y2225	LSIQRYAVIPL	4	Homo sapiens, Oryza sativa subsp. japonica, Mus musculus, Rattus norvegicus
Y2225	LSIQRYSVIPL	1	Arabidopsis thaliana
Y2225	LDIQQYPAIPL	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
Y2225	LSIQRYPVIPL	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)