General Information of Drug Off-Target (DOT) (ID: OTPAS4LF)

DOT Name cGMP-dependent protein kinase 1 (PRKG1)
Synonyms cGK 1; cGK1; EC 2.7.11.12; cGMP-dependent protein kinase I; cGKI
Gene Name PRKG1
Related Disease
Aortic aneurysm, familial thoracic 8 ( )
Familial thoracic aortic aneurysm and aortic dissection ( )
UniProt ID
KGP1_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
1ZXA; 3NMD; 3OCP; 3OD0; 3OGJ; 4KU7; 4KU8; 4QX5; 4QXK; 4R4L; 4R4M; 4Z07; 5J48; 5JAX; 5JD7; 5L0N; 6BDL; 6BG2; 6C0T; 7LV3; 7MBJ; 7SSB; 7T4T; 7T4U; 7T4V; 7T4W
EC Number
2.7.11.12
Pfam ID
PF00027 ; PF16808 ; PF00069
Sequence
MSELEEDFAKILMLKEERIKELEKRLSEKEEEIQELKRKLHKCQSVLPVPSTHIGPRTTR
AQGISAEPQTYRSFHDLRQAFRKFTKSERSKDLIKEAILDNDFMKNLELSQIQEIVDCMY
PVEYGKDSCIIKEGDVGSLVYVMEDGKVEVTKEGVKLCTMGPGKVFGELAILYNCTRTAT
VKTLVNVKLWAIDRQCFQTIMMRTGLIKHTEYMEFLKSVPTFQSLPEEILSKLADVLEET
HYENGEYIIRQGARGDTFFIISKGTVNVTREDSPSEDPVFLRTLGKGDWFGEKALQGEDV
RTANVIAAEAVTCLVIDRDSFKHLIGGLDDVSNKAYEDAEAKAKYEAEAAFFANLKLSDF
NIIDTLGVGGFGRVELVQLKSEESKTFAMKILKKRHIVDTRQQEHIRSEKQIMQGAHSDF
IVRLYRTFKDSKYLYMLMEACLGGELWTILRDRGSFEDSTTRFYTACVVEAFAYLHSKGI
IYRDLKPENLILDHRGYAKLVDFGFAKKIGFGKKTWTFCGTPEYVAPEIILNKGHDISAD
YWSLGILMYELLTGSPPFSGPDPMKTYNIILRGIDMIEFPKKIAKNAANLIKKLCRDNPS
ERLGNLKNGVKDIQKHKWFEGFNWEGLRKGTLTPPIIPSVASPTDTSNFDSFPEDNDEPP
PDDNSGWDIDF
Function
Serine/threonine protein kinase that acts as a 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 IRAG1 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.
Tissue Specificity Primarily expressed in lung and placenta.
KEGG Pathway
cGMP-PKG sig.ling pathway (hsa04022 )
Vascular smooth muscle contraction (hsa04270 )
Gap junction (hsa04540 )
Platelet activation (hsa04611 )
Circadian entrainment (hsa04713 )
Thermogenesis (hsa04714 )
Long-term depression (hsa04730 )
Olfactory transduction (hsa04740 )
Regulation of lipolysis in adipocytes (hsa04923 )
Salivary secretion (hsa04970 )
Reactome Pathway
(Name not found )
Ca2+ pathway (R-HSA-4086398 )

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Aortic aneurysm, familial thoracic 8 DISALTGF Strong Autosomal dominant [1]
Familial thoracic aortic aneurysm and aortic dissection DIS069FB Strong Autosomal dominant [2]
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Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
This DOT Affected the Drug Response of 1 Drug(s)
Drug Name Drug ID Highest Status Interaction REF
Methamphetamine DMPM4SK Approved cGMP-dependent protein kinase 1 (PRKG1) affects the response to substance of Methamphetamine. [13]
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12 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate increases the expression of cGMP-dependent protein kinase 1 (PRKG1). [3]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of cGMP-dependent protein kinase 1 (PRKG1). [4]
Vorinostat DMWMPD4 Approved Vorinostat increases the expression of cGMP-dependent protein kinase 1 (PRKG1). [5]
Triclosan DMZUR4N Approved Triclosan decreases the expression of cGMP-dependent protein kinase 1 (PRKG1). [6]
Testosterone enanthate DMB6871 Approved Testosterone enanthate affects the expression of cGMP-dependent protein kinase 1 (PRKG1). [7]
EXISULIND DMBY56U Phase 3 EXISULIND increases the expression of cGMP-dependent protein kinase 1 (PRKG1). [8]
CP-461 DMEYMTX Phase 2 CP-461 increases the expression of cGMP-dependent protein kinase 1 (PRKG1). [8]
Geldanamycin DMS7TC5 Discontinued in Phase 2 Geldanamycin increases the expression of cGMP-dependent protein kinase 1 (PRKG1). [10]
Bisphenol A DM2ZLD7 Investigative Bisphenol A increases the expression of cGMP-dependent protein kinase 1 (PRKG1). [11]
Trichostatin A DM9C8NX Investigative Trichostatin A increases the expression of cGMP-dependent protein kinase 1 (PRKG1). [5]
ELLAGIC ACID DMX8BS5 Investigative ELLAGIC ACID decreases the expression of cGMP-dependent protein kinase 1 (PRKG1). [12]
(5-(1-benzyl-1H-indazol-3-yl)furan-2-yl)methanol DM15P2G Investigative (5-(1-benzyl-1H-indazol-3-yl)furan-2-yl)methanol increases the expression of cGMP-dependent protein kinase 1 (PRKG1). [8]
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⏷ Show the Full List of 12 Drug(s)
1 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the methylation of cGMP-dependent protein kinase 1 (PRKG1). [9]
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References

1 One-pot (1-ethoxycarbonylcyclopropyl)triphenylphosphonium tetrafluoroborate ring-opening and Wittig reaction. Org Lett. 2011 Oct 7;13(19):5338-41. doi: 10.1021/ol202207f. Epub 2011 Sep 12.
2 Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
3 Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
4 Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
5 Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
6 Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
7 Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
8 Cyclic GMP-dependent protein kinase activation and induction by exisulind and CP461 in colon tumor cells. J Pharmacol Exp Ther. 2001 Nov;299(2):583-92.
9 Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
10 Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
11 Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
12 Interactive gene expression pattern in prostate cancer cells exposed to phenolic antioxidants. Life Sci. 2002 Mar 1;70(15):1821-39.
13 Genome-wide association for methamphetamine dependence: convergent results from 2 samples. Arch Gen Psychiatry. 2008 Mar;65(3):345-55. doi: 10.1001/archpsyc.65.3.345.