Molecular Target Synopsis
Overview
Domains and Structures
Drugs and Clinical Candidates
Druggability
Chemistry
Ligand Efficiency Plot
Pathways
Family Cladogram
Interaction Network
Gene Expression
Gene Copy Number Variation
RNAi
Mutations
Germline Genetics

PRKG1 (Q13976) - Overview - Molecular Target Synopsis

Protein


PRKG1, cGMP-dependent protein kinase 1
Enzyme Classification 2.7.11.12
UniProt Q13976

Also Known as KGP1_HUMAN, PRKG1, PRKG1B, PRKGR1A, PRKGR1B

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. Isoform alpha: parallel homodimer or heterodimer and also heterotetramer. Interacts directly with PPP1R12A. Non-covalent dimer of dimer of PRKG1-PRKG1 and PPP1R12A-PPP1R12A. This interaction targets PRKG1 to stress fibers to mediate smooth muscle cell relaxation and vasodilation in responses to rises in cGMP. Isoform beta: antiparallel homodimer. Part of cGMP kinase signaling complex at least composed of ACTA2/alpha-actin, CNN1/calponin H1, PLN/phospholamban, PRKG1 and ITPR1 (By similarity). Interacts with MRVI1. Forms a stable complex with ITPR1, MRVI1, and isoform beta of PRKG1. Interacts with TRPC7 (via ankyrin repeat domain). Isoform alpha interacts with RGS2. Interacts with GTF2I.

6BG2
CRYSTAL STRUCTURE OF CGMP-DEPENDENT PROTEIN KINASE IALPHA (PKG IALPHA) CATALYTIC DOMAIN IN AMP-PNP BOUND STATE
RCSB/PDB
Inspect Structure
See all 3D Structures for PRKG1

Isoforms / Transcripts (Protein Coding)


Sub-cellular localization


UniProt: PRKG1 is active in the following subcellular-locations: cytoplasm.
GO terms: PRKG1 is active in the following subcellular-locations: cytoplasm, cytosol, Golgi apparatus, plasma membrane.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project PRKG1 has gain in 5 cell-lines, loss in 1 cell-lines and no signal in 998 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: TK_10, BT_549, MCF7

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: LXFL529, Hs 746T, U266B1

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: NHLF, AG445, HFDPC

(see details)

RNA Interference


PRKG1 was reported in the following RNAI studies:

Cell - Large Scale Profiling of Kinase Dependencies in Cancer Cell Lines, the highest RNAi cell lines are: BEN, KPD. (see details)

3D Structures


For PRKG1 there are:
19 structures (42 chains) solved
15 are solved in complex with at least one small molecule ligand



(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


PRKG1 has been screened with 691 compounds (1634 bioactivities), 12 compounds have bioactivities that show binding affinity of <= 500nM (20 bioactivities). (see details)