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Protein kinase G (PKG) 1

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Target id: 1492

Nomenclature: Protein kinase G (PKG) 1

Abbreviated Name: PKG1

Family: Protein kinase G (PKG) family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 671 10q11.23-q21.1 PRKG1 protein kinase cGMP-dependent 1
Mouse - 671 19 C1 Prkg1 protein kinase, cGMP-dependent, type I
Rat - 671 1 q52 Prkg1 protein kinase cGMP-dependent 1
Gene and Protein Information Comments
Two protein isoforms that differ in their N-terminal sequences are generated from the human PRKG1 gene: PKG1α and PKG1β [10].
Previous and Unofficial Names Click here for help
PGK | PKG | PRKG1B | PRKGR1B | cGk1 | Prkg1b | protein kinase | protein kinase, cGMP-dependent, type I
Database Links Click here for help
Alphafold Q13976 (Hs), P0C605 (Mm)
BRENDA 2.7.11.12
CATH/Gene3D 2.60.120.10
ChEMBL Target CHEMBL4273 (Hs)
Ensembl Gene ENSG00000185532 (Hs), ENSMUSG00000052920 (Mm), ENSRNOG00000053728 (Rn)
Entrez Gene 5592 (Hs), 19091 (Mm)
Human Protein Atlas ENSG00000185532 (Hs)
KEGG Enzyme 2.7.11.12
KEGG Gene hsa:5592 (Hs), mmu:19091 (Mm)
OMIM 176894 (Hs)
Orphanet ORPHA363279 (Hs)
Pharos Q13976 (Hs)
RefSeq Nucleotide NM_001098512 (Hs), NM_001013833 (Mm), NM_001105731 (Rn)
RefSeq Protein NP_006249 (Hs), NP_001091982 (Hs), NP_035290 (Mm), NP_001013855 (Mm), NP_001099201 (Rn)
UniProtKB Q13976 (Hs), P0C605 (Mm)
Wikipedia PRKG1 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of cAMP bound cGMP-dependent protein kinase(92-227)
PDB Id:  3OCP
Resolution:  2.49Å
Species:  Human
References:  8
Enzyme Reaction Click here for help
EC Number: 2.7.11.12

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
aplithianine A Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.0 pIC50 5
⤷ pIC50 8.0 (IC50 1.1x10-8 M) [5]
Description: Inhibition of PGK1α
GSK690693 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.5 pIC50 7
⤷ pIC50 7.5 (IC50 3.3x10-8 M) [7]
ipatasertib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.2 pIC50 2
⤷ pIC50 7.2 (IC50 6.9x10-8 M) [2]
Rp-8-CPT-cGMPS Small molecule or natural product Hs Inhibition - - 3
⤷ [3]
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
allosteric modulator 33 [PMID: 35878399] Small molecule or natural product Ligand has a PDB structure Hs Activation 6.3 pEC50 9
⤷ pEC50 6.3 (EC50 5.2x10-7 M) [9]
Description: Kinase activity determined for partially activated recombinant hPKG1α (with cGMP at EC20 concentration)
Allosteric Modulator Comments
The equivalent pEC50 value for allosteric modulator 33 [PMID: 35878399]-mediated kinase activation of partially activated recombinant hPKG1β isoform is 5.2 [9].
DiscoveRx KINOMEscan® screen Click here for help
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 4,11
Key to terms and symbols Click column headers to sort
Target used in screen: PRKG1
Ligand Sp. Type Action Value Parameter
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.5 pKd
GSK690693 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.7 pKd
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.6 pKd
A-674563 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.6 pKd
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.4 pKd
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.4 pKd
enzastaurin Small molecule or natural product Hs Inhibitor Inhibition 6.0 pKd
KW-2449 Small molecule or natural product Hs Inhibitor Inhibition 5.6 pKd
SB203580 Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition <5.5 pKd
ruboxistaurin Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition <5.5 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen Click here for help
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx

Reference: 1,6
Key to terms and symbols Click column headers to sort
Target used in screen: PKG1α/PKG1a
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 5.0 3.0 3.0
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.4 8.0 4.0
K-252a Small molecule or natural product Hs Inhibitor Inhibition 13.4 10.0 1.0
PKR inhibitor Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 17.5 13.0 2.0
H-89 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 26.3 4.0 4.0
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 35.7 84.0 73.0
GF109203X Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 38.3 60.0 14.0
JAK inhibitor I Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 40.2 45.0 45.0
indirubin derivative E804 Small molecule or natural product Hs Inhibitor Inhibition 45.1 56.0 19.0
dorsomorphin Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 57.6 73.0 25.0
Target used in screen: PKG1β/PKG1b
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 3.3 1.0 0.5
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 18.8 4.0 3.0
K-252a Small molecule or natural product Hs Inhibitor Inhibition 19.1 9.0 2.0
PKR inhibitor Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 20.3 7.0 1.0
H-89 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 41.1 4.0 4.0
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 41.3 76.0 74.0
JAK inhibitor I Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 52.3 30.0 19.0
indirubin derivative E804 Small molecule or natural product Hs Inhibitor Inhibition 53.0 44.0 9.0
JAK3 inhibitor VI Small molecule or natural product Hs Inhibitor Inhibition 58.7 39.0 7.0
GF109203X Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 59.3 34.0 6.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Aortic aneurysm, familial thoracic 8; AAT8
Synonyms: Familial thoracic aortic aneurysm and aortic dissection [Orphanet: ORPHA91387]
thoracic aortic aneurysm
Disease Ontology: DOID:14004
OMIM: 615436
Orphanet: ORPHA91387
General Comments
PRKG1 is involved in mediating the physiological effects of soluble guanylate cyclases (sGC)-derived cGMP. Two protein isoforms that differ in their N-terminal sequences are generated from the human PRKG1 gene: PKG1α and PKG1β [10]. Both isoforms have identical cGMP binding sites and catalytic domains, and are highly expressed in smooth muscle. The α isoform is the primary isoform that's expressed in the heart and lungs. PKG1α's N-terminal region contributes to its high affinity for cGMP. Activation of PKG1α is being examined as a mechanism for the treatment of cardiovascular diseases.

References

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1. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1039-45. [PMID:22037377]

2. Blake JF, Xu R, Bencsik JR, Xiao D, Kallan NC, Schlachter S, Mitchell IS, Spencer KL, Banka AL, Wallace EM et al.. (2012) Discovery and preclinical pharmacology of a selective ATP-competitive Akt inhibitor (GDC-0068) for the treatment of human tumors. J Med Chem, 55 (18): 8110-27. [PMID:22934575]

3. Butt E, Eigenthaler M, Genieser HG. (1994) (Rp)-8-pCPT-cGMPS, a novel cGMP-dependent protein kinase inhibitor. Eur J Pharmacol, 269 (2): 265-8. [PMID:7851503]

4. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1046-51. [PMID:22037378]

5. Du L, Wilson BAP, Li N, Shah R, Dalilian M, Wang D, Smith EA, Wamiru A, Goncharova EI, Zhang P et al.. (2023) Discovery and Synthesis of a Naturally Derived Protein Kinase Inhibitor that Selectively Inhibits Distinct Classes of Serine/Threonine Kinases. J Nat Prod, 86 (10): 2283-2293. [PMID:37843072]

6. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ. (2013) A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem J, 451 (2): 313-28. [PMID:23398362]

7. Heerding DA, Rhodes N, Leber JD, Clark TJ, Keenan RM, Lafrance LV, Li M, Safonov IG, Takata DT, Venslavsky JW et al.. (2008) Identification of 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a novel inhibitor of AKT kinase. J Med Chem, 51 (18): 5663-79. [PMID:18800763]

8. Kim JJ, Casteel DE, Huang G, Kwon TH, Ren RK, Zwart P, Headd JJ, Brown NG, Chow DC, Palzkill T et al.. (2011) Co-crystal structures of PKG Iβ (92-227) with cGMP and cAMP reveal the molecular details of cyclic-nucleotide binding. PLoS ONE, 6 (4): e18413. [PMID:21526164]

9. Mak VW, Patel AM, Yen R, Hanisak J, Lim YH, Bao J, Zheng R, Seganish WM, Yu Y, Healy DR et al.. (2022) Optimization and Mechanistic Investigations of Novel Allosteric Activators of PKG1α. J Med Chem, 65 (15): 10318-10340. [PMID:35878399]

10. Ruth P, Pfeifer A, Kamm S, Klatt P, Dostmann WR, Hofmann F. (1997) Identification of the amino acid sequences responsible for high affinity activation of cGMP kinase Ialpha. J Biol Chem, 272 (16): 10522-8. [PMID:9099696]

11. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem Biol, 17 (11): 1241-9. [PMID:21095574]

How to cite this page

Protein kinase G (PKG) family: Protein kinase G (PKG) 1. Last modified on 11/01/2024. Accessed on 19/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=1492.