Tchem PRKG1 cGMP-dependent protein kinase 1

Protein Classes

DTO Classes

Protein / Kinase / Protein Kinase / Agc Group / Pkg Family / Cgmp-dependent Protein Kinase 1

Protein Summary

Description

Serine/threonine protein kinase that acts as key mediator of the nitric oxide (NO)/cGMP signaling pathway. GMP binding activates PRKG1, which phosphorylates serines and threonines on many cellular proteins. Numerous protein targets for PRKG1 phosphorylation are implicated in modulating cellular calcium, but the contribution of each of these targets may vary substantially among cell types. Proteins that are phosphorylated by PRKG1 regulate platelet activation and adhesion, smooth muscle contraction, cardiac function, gene expression, feedback of the NO-signaling pathway, and other processes involved in several aspects of the CNS like axon guidance, hippocampal and cerebellar learning, circadian rhythm and nociception. Smooth muscle relaxation is mediated through lowering of intracellular free calcium, by desensitization of contractile proteins to calcium, and by decrease in the contractile state of smooth muscle or in platelet activation. Regulates intracellular calcium levels via several pathways: phosphorylates MRVI1/IRAG and inhibits IP3-induced Ca(2+) release from intracellular stores, phosphorylation of KCNMA1 (BKCa) channels decreases intracellular Ca(2+) levels, which leads to increased opening of this channel. PRKG1 phosphorylates the canonical transient receptor potential channel (TRPC) family which inactivates the associated inward calcium current. Another mode of action of NO/cGMP/PKGI signaling involves PKGI-mediated inactivation of the Ras homolog gene family member A (RhoA). Phosphorylation of RHOA by PRKG1 blocks the action of this protein in myriad processes: regulation of RHOA translocation; decreasing contraction; controlling vesicle trafficking, reduction of myosin light chain phosphorylation resulting in vasorelaxation. Activation of PRKG1 by NO signaling alters also gene expression in a number of tissues. In smooth muscle cells, increased cGMP and PRKG1 activity influence expression of smooth muscle-specific contractile proteins, levels of proteins in the NO/cGMP signaling pathway, down-regulation of the matrix proteins osteopontin and thrombospondin-1 to limit smooth muscle cell migration and phenotype. Regulates vasodilator-stimulated phosphoprotein (VASP) functions in platelets and smooth muscle. Mammals have three different isoforms of cyclic GMP-dependent protein kinase (Ialpha, Ibeta, and II). These PRKG isoforms act as key mediators of the nitric oxide/cGMP signaling pathway and are important components of many signal transduction processes in diverse cell types. This PRKG1 gene on human chromosome 10 encodes the soluble Ialpha and Ibeta isoforms of PRKG by alternative transcript splicing. A separate gene on human chromosome 4, PRKG2, encodes the membrane-bound PRKG isoform II. The PRKG1 proteins play a central role in regulating cardiovascular and neuronal functions in addition to relaxing smooth muscle tone, preventing platelet aggregation, and modulating cell growth. This gene is most strongly expressed in all types of smooth muscle, platelets, cerebellar Purkinje cells, hippocampal neurons, and the lateral amygdala. Isoforms Ialpha and Ibeta have identical cGMP-binding and catalytic domains but differ in their leucine/isoleucine zipper and autoinhibitory sequences and therefore differ in their dimerization substrates and kinase enzyme activity. [provided by RefSeq, Sep 2011]

Uniprot Accession IDs

• Q13976
• A5YM56
• B3KSF3
• E2PU10
• P14619
• Q5JP05
• Q5JSJ6
• Q6P5T7
• cGK 1

Gene Name

• PRKG1

Ensembl ID

• ENST00000373980
• ENSP00000363092
• ENSG00000185532
• ENST00000373985
• ENSP00000363097
• ENST00000401604
• ENSP00000384200
• ENST00000646535
• ENSP00000493966

Symbol

• PRKG1B
• PRKGR1A
• PRKGR1B
• PKG
• cGK
• AAT8
• PKG1
• cGK1
• cGKI
• cGK 1
• PRKG1B
• PRKGR1B
• cGKI-BETA
• cGKI-alpha

Knowledge Table

Most Knowledge About	Knowledge Value (0 to 1 scale)
protein domain	1
trait	1
molecular function	0.99
gene perturbation	0.89
hub protein	0.82

Related Tools

ProKinO

The ProKinO is a protein kinase-specific ontology, which provides a controlled vocabulary of terms, their hierarchy, and relationships unifying sequence, structure, function, mutation and pathway information on kinases.

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Target Illumination GWAS Analytics (TIGA)

TIGA scores and ranks GWAS discovered associations according to the quantity and quality of the evidence supporting the association.

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GENEVA

GENEVA (GENe Expression Variance Analysis) allows you to identify RNA-sequencing datasets from the Gene Expression Omnibus (GEO) that contain conditions modulating a gene or a gene signature.

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GlyGen

GlyGen is a data integration and dissemination project for carbohydrate and glycoconjugate related data.

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ARCHS4

ARCHS4 provides access to gene-function predictions based on RNA-seq co-expression, and gene expression levels across cell and tissues.

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IDG Development Level Summary

Tdark

These are targets about which virtually nothing is known. They do not have known drug or small molecule activities
- AND - satisfy two or more of the following criteria:

Pubmed score: 601.77   (req: < 5)

Gene RIFs: 94   (req: <= 3)

Antibodies: 306   (req: <= 50)

Tbio

These targets do not have known drug or small molecule activities
- AND - satisfy two or more of the following criteria:

Pubmed score: 601.77   (req: >= 5)

Gene RIFs: 94   (req: > 3)

Antibodies: 306   (req: > 50)

- OR - satisfy the following criterion:

Gene Ontology Terms: 19

Tchem

Target has at least one ChEMBL compound with an activity cutoff of < 30 nM - AND - satisfies the preceding conditions

Active Ligands: 7

Tclin

Target has at least one approved drug - AND - satisfies the preceding conditions

Active Drug: 1

Approved Drugs (1)

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1 – 1 of 1

nintedanib

PRKG1Tchem Kinase

Kd : 7.85

Active Ligands (7)

Explore Active Ligands

1 – 7 of 7

CHEMBL388978

PRKG1Tchem Kinase

IC50 : 8.3

CHEMBL494089

PRKG1Tchem Kinase

IC50 : 7.48000002

CHEMBL60254

PRKG1Tchem Kinase

Kd : 8.8

CHEMBL2023841

PRKG1Tchem Kinase

Kd : 8.89

CHEMBL2177390

PRKG1Tchem Kinase

IC50 : 7.15999985

CHEMBL2023714

PRKG1Tchem Kinase

Kd : 7.89

CHEMBL2023845

PRKG1Tchem Kinase

Kd : 8.49

GWAS Traits (10)

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GWAS Trait	EFO ID	Study Count	SNP Count	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
body mass index	EFO_0004340	2	1	2		73.1
schizophrenia	EFO_0000692	2	2	0	1.1	68.6
self reported educational attainment	EFO_0004784	2	2	2		67.9
mathematical ability	EFO_0004875	1	1	1		61.5
alcohol dependence measurement	EFO_0007835	1	1	0	5.6	59.2

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GWAS Trait	EFO ID	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
body mass index	EFO_0004340	2		73.1
schizophrenia	EFO_0000692	0	1.1	68.6
self reported educational attainment	EFO_0004784	2		67.9
mathematical ability	EFO_0004875	1		61.5
alcohol dependence measurement	EFO_0007835	0	5.6	59.2

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Orthologs (11)

1 – 5 of 11

Species	Name	Source ID	Gene ID	OMA	EggNOG	Inparanoid
Chimp	protein kinase, cGMP-dependent, type I		744467
Macaque	protein kinase, cGMP-dependent, type I		703356
Mouse	protein kinase, cGMP-dependent, type I	MGI:108174	19091
Dog	protein kinase cGMP-dependent 1	VGNC:49948	609616
Horse	protein kinase, cGMP-dependent, type I [Source:HGNC Symbol;Acc:HGNC:9414]

Species	Name	OMA	EggNOG	Inparanoid
Chimp	protein kinase, cGMP-dependent, type I
Macaque	protein kinase, cGMP-dependent, type I
Mouse	protein kinase, cGMP-dependent, type I
Dog	protein kinase cGMP-dependent 1
Horse	protein kinase, cGMP-dependent, type I [Source:HGNC Symbol;Acc:HGNC:9414]

Protein Structure (18 Structures, 1 AlphaFold Model)

Representation

  axes   backbone   ball+stick   cartoon   rocket   rope   spacefill

Color Scheme

  target   atomindex   bfactor   chainname   electrostatic   element   hydrophobicity   resname   sstruc

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More information can be found at RCSB PDB

AF-Q13976-F1-model_v1

AlphaFold Structures Developed by DeepMind and EMBL-EBI

1 – 5 of 18

PDB Structure Id	Ligand	Method	Resolution (Å)	Residues	Fraction of Total Protein	Pub Year	Title

PDB Structure Id	Fraction of Total Protein	Resolution	Pub Year

Pathways (34)

Reactome (11)

KEGG (10)

PathwayCommons (9)

WikiPathways (4)

Adaptive Immune System (R-HSA-1280218)

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Find Similar Targets

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Data Source	Name	Explore in Pharos	Explore in Source
Reactome	Adaptive Immune System	894 targets	R-HSA-1280218
Reactome	Beta-catenin independent WNT signaling	146 targets	R-HSA-3858494
Reactome	Ca2+ pathway	61 targets	R-HSA-4086398
Reactome	Hemostasis	666 targets	R-HSA-109582
Reactome	Immune System	2246 targets	R-HSA-168256

Name	Explore in Pharos	Explore in Source
Adaptive Immune System	894 targets	R-HSA-1280218
Beta-catenin independent WNT signaling	146 targets	R-HSA-3858494
Ca2+ pathway	61 targets	R-HSA-4086398
Hemostasis	666 targets	R-HSA-109582
Immune System	2246 targets	R-HSA-168256

Gene Ontology Terms (23)

Functions (7)

Components (4)

Processes (12)

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10

1 – 7 of 7

GO Term	Evidence	Assigned by
calcium channel regulator activity	Inferred from Direct Assay (IDA)	UniProtKB
cGMP-dependent protein kinase activity	Inferred from Direct Assay (IDA)	UniProtKB
identical protein binding	Inferred from Physical Interaction (IPI)	IntAct
protein kinase activity	Inferred from Mutant Phenotype (IMP)	BHF-UCL
protein serine/threonine kinase activity	Traceable Author Statement (TAS)	Reactome
ATP binding	Inferred from Electronic Annotation (IEA)	UniProtKB-KW
cGMP binding	Inferred from Electronic Annotation (IEA)	UniProtKB-KW

Protein-Protein Interactions (232)

Explore Interacting Targets

1 – 10 of 232

• See Interactions on String-DB

PTK2

Tclin

Family: Kinase

Novelty: 0.00066622

p_int: 0.999999384

p_ni: 6.16e-7

Score: 0.461

Data Source: BioPlex,STRINGDB

ZKSCAN1

Tbio

Family: TF

Novelty: 0.08190662

p_int: 0.999998606

p_ni: 0.000001393

Score: 0.242

Data Source: BioPlex,STRINGDB

OAS2

Tbio

Family: Enzyme

Novelty: 0.01673393

p_int: 0.999950623

p_ni: 0.000049377

Score: 0.428

Data Source: BioPlex,STRINGDB

CORO2B

Tdark

Novelty: 0.30665394

p_int: 0.999485994

p_ni: 0.000514005

p_wrong: 1e-9

Score: 0.397

Data Source: BioPlex,STRINGDB

TNNT1

Tbio

Novelty: 0.00072003

p_int: 0.998406196

p_ni: 0.001593803

p_wrong: 1e-9

Score: 0.496

Data Source: BioPlex,STRINGDB

PSMC5

Tbio

Family: Enzyme

Novelty: 0.01634039

p_int: 0.837129559

p_ni: 0.16286295

p_wrong: 0.000007491

Score: 0.196

Data Source: BioPlex,STRINGDB

MRVI1

Tbio

Novelty: 0.02987514

Score: 0.994

Data Source: Reactome,STRINGDB

VASP

Tbio

Novelty: 0.00041984

Score: 0.982

Data Source: STRINGDB

GKAP1

Tdark

Family: Enzyme

Novelty: 0.35828233

Score: 0.971

Data Source: STRINGDB

RGS2

Tbio

Novelty: 0.00370571

Score: 0.957

Data Source: STRINGDB

Publication Statistics

PubMed Score  601.77

PubMed score by year

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PubTator Score  546.81

PubTator score by year

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Patents

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Amino Acid Sequence

Residue Counts

Protein Sequence

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Ortholog Sequence Conservation

WebLogo Color Code

PolarG S T Y C

NeutralQ N

BasicK R H

AcidicD E

HydrophobicA V L I P W F M

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Structural Annotations

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UniProt Keyword Find Similar Targets

3D-structure
Acetylation
Allosteric enzyme
Alternative splicing
Aortic aneurysm
ATP-binding
cGMP
cGMP-binding
Coiled coil
Complete proteome

GWAS Trait Find Similar Targets

alcohol dependence measurement
autism spectrum disorder
body height
body mass index
interferon alpha measurement
mathematical ability
schizophrenia
self reported educational attainment
stressful life event measurement
systemic lupus erythematosus

MGI Phenotype Find Similar Targets

adipose tissue phenotype
cardiovascular system phenotype
cellular phenotype
digestive/alimentary phenotype
hematopoietic system phenotype
homeostasis/metabolism phenotype
immune system phenotype
mortality/aging
muscle phenotype
nervous system phenotype