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 PDE2A

Gene summary

Basic gene Info.	Gene symbol	PDE2A
	Gene name	phosphodiesterase 2A, cGMP-stimulated
	Synonyms	CGS-PDE\|PDE2A1\|PED2A4\|cGSPDE
	Cytomap	UCSC genome browser: 11q13.4
	Type of gene	protein-coding
	RefGenes	NM_001143839.3, NM_001146209.2,NM_001243784.1,NM_002599.4,
	Description	cGMP-dependent 3',5'-cyclic phosphodiesterasecGMP-stimulated phosphodiesterase 1cGMP-stimulated phosphodiesterase 4cyclic GMP-stimulated phosphodiesterase
	Modification date	20141207
dbXrefs	MIM : 602658
	HGNC : HGNC
	Ensembl : ENSG00000186642
	HPRD : 04041
	Vega : OTTHUMG00000102045
Protein	UniProt: O00408 go to UniProt's Cross Reference DB Table
Expression	CleanEX: HS_PDE2A
	BioGPS: 5138
Pathway	NCI Pathway Interaction Database: PDE2A
	KEGG: PDE2A
	REACTOME: PDE2A
	Pathway Commons: PDE2A
Context	iHOP: PDE2A
	ligand binding site mutation search in PubMed: PDE2A
	UCL Cancer Institute: PDE2A
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 PDE2A.	1. Heikaus, C. C., Stout, J. R., Sekharan, M. R., Eakin, C. M., Rajagopal, P., Brzovic, P. S., ... & Klevit, R. E. (2008). Solution Structure of the cGMP Binding GAF Domain from Phosphodiesterase 5 INSIGHTS INTO NUCLEOTIDE SPECIFICITY, DIMERIZATION, AND cGMP-DEPENDENT CONFORMATIONAL CHANGE. Journal of Biological Chemistry, 283(33), 22749-22759. 18534985

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

GO ID	GO Term	PubMed ID
GO:0000122	negative regulation of transcription from RNA polymerase II promoter	17329248
GO:0006198	cAMP catabolic process	14687666
GO:0008152	metabolic process	17329248
GO:0033159	negative regulation of protein import into nucleus, translocation	17329248
GO:0036006	cellular response to macrophage colony-stimulating factor stimulus	14687666
GO:0046069	cGMP catabolic process	14687666
GO:0071321	cellular response to cGMP	17704206
GO:0097011	cellular response to granulocyte macrophage colony-stimulating factor stimulus	14687666

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Ligand binding site mutations for PDE2A

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
I866	A867V	COAD	1
I822	K821R	KIRC	1
N704	T703R	LUAD	1
N704	N704S	LUAD	1
L774	I776M	LUSC	1
Y655	P653T	LUSC	1
I866	A867V	OV	1
M847,M845	E846K	SKCM	1
N704	N704Y	STAD	1
N704,H700	G702C	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 PDE2A

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
N704	N704Y	0.21625259
N704	N704S	0.008137558
L774	I776M	-1.5330969
M845	E846K	-1.2817133
M847	E846K	-1.2817133
I866	A867V	-1.1876784
N704	T703R	-1.0810062
Y655	P653T	-1.0619263
N704	G702C	-0.48538548
H700	G702C	-0.48538548
I822	K821R	-0.38224486

(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 PDE2A from PDB

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Differential gene expression and gene-gene network for PDE2A

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 PDE2A and the right PPI network was created from samples without mutations in the LBS of PDE2A. 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 PDE2A

Gene level disease information (DisGeNet)

Disease ID	Disease name	# PubMed	Association type
umls:C1458155	Breast 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 PDE2A

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	DB02315	Cyclic Guanosine Monophosphate	Small molecule
Investigational	DB05142	ND7001	Small molecule
Experimental	DB07954	3-isobutyl-1-methyl-7H-xanthine	Small molecule
Approved	DB08811	Tofisopam	Small molecule

Gene-centered ligand-gene interaction network

Ligands binding to mutated ligand binding site of PDE2A go to BioLip

Ligand ID	Ligand short name	Ligand long name	PDB ID	PDB name	mutLBS
MG		MAGNESIUM(2+)	4d09	C	H700
MG		MAGNESIUM(2+)	4d09	D	H700
EH9		(2S,3R)-EHNA	4c1i	D	I866
788		N-BENZYL-4-METHYL-1-PHENYL[1,2,4]TRIAZOLO[4, 3-A]QUINOXALINE-8-CARBOXAMIDE	4d09	D	L774 I822 M847
788		N-BENZYL-4-METHYL-1-PHENYL[1,2,4]TRIAZOLO[4, 3-A]QUINOXALINE-8-CARBOXAMIDE	4d09	A	L774 M847
Q2T		1-(5-BUTOXYPYRIDIN-3-YL)-4-METHYL-8- (MORPHOLIN-4-YLMETHYL)[1,2,4]TRIAZOLO[4,3-A] QUINOXALINE	4d08	C	M845 M847
788		N-BENZYL-4-METHYL-1-PHENYL[1,2,4]TRIAZOLO[4, 3-A]QUINOXALINE-8-CARBOXAMIDE	4d09	B	M847
Q2T		1-(5-BUTOXYPYRIDIN-3-YL)-4-METHYL-8- (MORPHOLIN-4-YLMETHYL)[1,2,4]TRIAZOLO[4,3-A] QUINOXALINE	4d08	D	N704 M845 M847
Q2T		1-(5-BUTOXYPYRIDIN-3-YL)-4-METHYL-8- (MORPHOLIN-4-YLMETHYL)[1,2,4]TRIAZOLO[4,3-A] QUINOXALINE	4d08	A	N704 M847
Q2T		1-(5-BUTOXYPYRIDIN-3-YL)-4-METHYL-8- (MORPHOLIN-4-YLMETHYL)[1,2,4]TRIAZOLO[4,3-A] QUINOXALINE	4d08	B	N704 M847
IBM		3-ISOBUTYL-1-METHYL-9H-XANTHINE	3itu	B	Y655
IBM		3-ISOBUTYL-1-METHYL-9H-XANTHINE	3itu	C	Y655
IBM		3-ISOBUTYL-1-METHYL-9H-XANTHINE	3itu	D	Y655
EH9		(2S,3R)-EHNA	4c1i	A	Y655
EH9		(2S,3R)-EHNA	4c1i	C	Y655
1L6		1-(2-HYDROXYETHYL)-3-(2-METHYLBUTAN-2-YL)-5-[4-(2- METHYL-1H-IMIDAZOL-1-YL)PHENYL]-6,7-DIHYDROPYRAZOLO[4, 3-E][1,4]DIAZEPIN-8(1H)-ONE	4jib	B	Y655 I822 M847 I866
EH9		(2S,3R)-EHNA	4c1i	B	Y655 I866
788		N-BENZYL-4-METHYL-1-PHENYL[1,2,4]TRIAZOLO[4, 3-A]QUINOXALINE-8-CARBOXAMIDE	4d09	C	Y655 L774 M847 I866
IBM		3-ISOBUTYL-1-METHYL-9H-XANTHINE	3itu	A	Y655 M847
1L6		1-(2-HYDROXYETHYL)-3-(2-METHYLBUTAN-2-YL)-5-[4-(2- METHYL-1H-IMIDAZOL-1-YL)PHENYL]-6,7-DIHYDROPYRAZOLO[4, 3-E][1,4]DIAZEPIN-8(1H)-ONE	4jib	A	Y655 M847
1L6		1-(2-HYDROXYETHYL)-3-(2-METHYLBUTAN-2-YL)-5-[4-(2- METHYL-1H-IMIDAZOL-1-YL)PHENYL]-6,7-DIHYDROPYRAZOLO[4, 3-E][1,4]DIAZEPIN-8(1H)-ONE	4jib	C	Y655 M847
1L6		1-(2-HYDROXYETHYL)-3-(2-METHYLBUTAN-2-YL)-5-[4-(2- METHYL-1H-IMIDAZOL-1-YL)PHENYL]-6,7-DIHYDROPYRAZOLO[4, 3-E][1,4]DIAZEPIN-8(1H)-ONE	4jib	D	Y655 M847
19F	BAY60-7550	2-(3,4-DIMETHOXYBENZYL)-7-[(2R,3R)-2-HYDROXY-6- PHENYLHEXAN-3-YL]-5-METHYLIMIDAZO[5,1-F][1,2, 4]TRIAZIN-4(3H)-ONE	4htx	A	Y655 M847 I866
19F	BAY60-7550	2-(3,4-DIMETHOXYBENZYL)-7-[(2R,3R)-2-HYDROXY-6- PHENYLHEXAN-3-YL]-5-METHYLIMIDAZO[5,1-F][1,2, 4]TRIAZIN-4(3H)-ONE	4htx	B	Y655 M847 I866
19F	BAY60-7550	2-(3,4-DIMETHOXYBENZYL)-7-[(2R,3R)-2-HYDROXY-6- PHENYLHEXAN-3-YL]-5-METHYLIMIDAZO[5,1-F][1,2, 4]TRIAZIN-4(3H)-ONE	4htx	C	Y655 M847 I866
19F	BAY60-7550	2-(3,4-DIMETHOXYBENZYL)-7-[(2R,3R)-2-HYDROXY-6- PHENYLHEXAN-3-YL]-5-METHYLIMIDAZO[5,1-F][1,2, 4]TRIAZIN-4(3H)-ONE	4htx	D	Y655 M847 I866

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Conservation information for LBS of PDE2A

Multiple alignments for O00408 in multiple species

LBS	AA sequence	# species	Species
D697	SCMCHDLDHRG	3	Homo sapiens, Rattus norvegicus, Bos taurus
D808	LMTSCDLSDQT	3	Homo sapiens, Rattus norvegicus, Bos taurus
D811	SCDLSDQTKGW	3	Homo sapiens, Rattus norvegicus, Bos taurus
E727	EGSVMERHHFA	3	Homo sapiens, Rattus norvegicus, Bos taurus
F830	LIYKEFFSQGD	3	Homo sapiens, Rattus norvegicus, Bos taurus
F862	ELQISFMEHIA	3	Homo sapiens, Rattus norvegicus, Bos taurus
H656	RDPPYHNWMHA	3	Homo sapiens, Rattus norvegicus, Bos taurus
H660	YHNWMHAFSVS	3	Homo sapiens, Rattus norvegicus, Bos taurus
H696	ISCMCHDLDHR	3	Homo sapiens, Rattus norvegicus, Bos taurus
H700	CHDLDHRGTNN	3	Homo sapiens, Rattus norvegicus, Bos taurus
H730	VMERHHFAQAI	3	Homo sapiens, Rattus norvegicus, Bos taurus
H773	TDLAHHLRIFK	3	Homo sapiens, Rattus norvegicus, Bos taurus
I822	KTTRKIAELIY	3	Homo sapiens, Rattus norvegicus, Bos taurus
I826	KIAELIYKEFF	3	Homo sapiens, Rattus norvegicus, Bos taurus
I866	SFMEHIAMPIY	3	Homo sapiens, Rattus norvegicus, Bos taurus
I870	HIAMPIYKLLQ	3	Homo sapiens, Rattus norvegicus, Bos taurus
L770	ILATDLAHHLR	3	Homo sapiens, Rattus norvegicus, Bos taurus
L774	DLAHHLRIFKD	3	Homo sapiens, Rattus norvegicus, Bos taurus
L809	MTSCDLSDQTK	3	Homo sapiens, Rattus norvegicus, Bos taurus
L858	AYIPELQISFM	3	Homo sapiens, Rattus norvegicus, Bos taurus
M845	MGNRPMEMMDR	3	Homo sapiens, Rattus norvegicus, Bos taurus
M847	NRPMEMMDREK	3	Homo sapiens, Rattus norvegicus, Bos taurus
M848	RPMEMMDREKA	3	Homo sapiens, Rattus norvegicus, Bos taurus
N704	DHRGTNNSFQV	3	Homo sapiens, Rattus norvegicus, Bos taurus
Q812	CDLSDQTKGWK	3	Homo sapiens, Rattus norvegicus, Bos taurus
Q859	YIPELQISFME	3	Homo sapiens, Rattus norvegicus, Bos taurus
S721	AALYSSEGSVM	3	Homo sapiens, Rattus norvegicus, Bos taurus
S861	PELQISFMEHI	3	Homo sapiens, Rattus norvegicus, Bos taurus
T768	DIILATDLAHH	3	Homo sapiens, Rattus norvegicus, Bos taurus
T805	LCLLMTSCDLS	3	Homo sapiens, Rattus norvegicus, Bos taurus
Y655	YRDPPYHNWMH	3	Homo sapiens, Rattus norvegicus, Bos taurus
Y827	IAELIYKEFFS	3	Homo sapiens, Rattus norvegicus, Bos taurus