| Structural highlights
6c0t is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | DMS, EE4, PGE |
| NonStd Res: | TPO |
| Related: | 6c0u |
| Gene: | PRKG1, PRKG1B, PRKGR1A, PRKGR1B (HUMAN) |
| Activity: | Transferase, with EC number 2.7.11.12 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[KGP1_HUMAN] 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.[1] [2] [3] [4] [5] [6] [7] [8] [9]
Publication Abstract from PubMed
Activation of PKG Ialpha in nociceptive neurons induces a long-term hyperexcitability that causes chronic pain. Recently, a derivative of the fungal metabolite balanol, N46, has been reported to inhibit PKG Ialpha with high potency and selectivity and attenuates thermal hyperalgesia and osteoarthritic pain. Here, we determined co-crystal structures of the PKG Ialpha C-domain and cAMP-dependent protein kinase (PKA) Calpha, each bound with N46, at 1.98 A and 2.65 A, respectively. N46 binds the active site with its external phenyl ring specifically interacting with the glycine-rich loop and the alphaC helix. Phe371 at the PKG Ialpha glycine-rich loop is oriented parallel to the phenyl ring of N46, forming a strong pi-stacking interaction, while the analogous Phe54 in PKA Calpha rotates 30 masculine and forms a weaker interaction. Structural comparison revealed that steric hindrance between the preceding Ser53 and the propoxy group of the phenyl ring may explain the weaker interaction with PKA Calpha. The analogous Gly370 in PKG Ialpha, however, causes little steric hindrance with Phe371. Moreover, Ile406 on the alphaC helix forms a hydrophobic interaction with N46 while its counterpart in PKA, Thr88, does not. Substituting these residues in PKG Ialpha with those in PKA Calpha increases its IC50 values for N46 whereas replacing these residues in PKA Calpha with those in PKG Ialpha reduces the IC50, consistent with our structural findings. In conclusion, our results explain the structural basis for N46-mediated selective inhibition of human PKG Ialpha and provide a starting point for structure-guided design of selective PKG Ialpha inhibitors.
Structural basis for selective inhibition of human PKG Ialpha by the balanol-like compound N46.,Qin L, Sankaran B, Aminzai S, Casteel D, Kim C J Biol Chem. 2018 May 16. pii: RA118.002427. doi: 10.1074/jbc.RA118.002427. PMID:29769318[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Butt E, Abel K, Krieger M, Palm D, Hoppe V, Hoppe J, Walter U. cAMP- and cGMP-dependent protein kinase phosphorylation sites of the focal adhesion vasodilator-stimulated phosphoprotein (VASP) in vitro and in intact human platelets. J Biol Chem. 1994 May 20;269(20):14509-17. PMID:8182057
- ↑ Surks HK, Mochizuki N, Kasai Y, Georgescu SP, Tang KM, Ito M, Lincoln TM, Mendelsohn ME. Regulation of myosin phosphatase by a specific interaction with cGMP- dependent protein kinase Ialpha. Science. 1999 Nov 19;286(5444):1583-7. PMID:10567269
- ↑ Sawada N, Itoh H, Yamashita J, Doi K, Inoue M, Masatsugu K, Fukunaga Y, Sakaguchi S, Sone M, Yamahara K, Yurugi T, Nakao K. cGMP-dependent protein kinase phosphorylates and inactivates RhoA. Biochem Biophys Res Commun. 2001 Jan 26;280(3):798-805. PMID:11162591 doi:10.1006/bbrc.2000.4194
- ↑ Casteel DE, Zhuang S, Gudi T, Tang J, Vuica M, Desiderio S, Pilz RB. cGMP-dependent protein kinase I beta physically and functionally interacts with the transcriptional regulator TFII-I. J Biol Chem. 2002 Aug 30;277(35):32003-14. Epub 2002 Jun 24. PMID:12082086 doi:10.1074/jbc.M112332200
- ↑ Rybalkin SD, Rybalkina IG, Feil R, Hofmann F, Beavo JA. Regulation of cGMP-specific phosphodiesterase (PDE5) phosphorylation in smooth muscle cells. J Biol Chem. 2002 Feb 1;277(5):3310-7. Epub 2001 Nov 26. PMID:11723116 doi:10.1074/jbc.M106562200
- ↑ Tang KM, Wang GR, Lu P, Karas RH, Aronovitz M, Heximer SP, Kaltenbronn KM, Blumer KJ, Siderovski DP, Zhu Y, Mendelsohn ME. Regulator of G-protein signaling-2 mediates vascular smooth muscle relaxation and blood pressure. Nat Med. 2003 Dec;9(12):1506-12. Epub 2003 Nov 9. PMID:14608379 doi:10.1038/nm958
- ↑ Wooldridge AA, MacDonald JA, Erdodi F, Ma C, Borman MA, Hartshorne DJ, Haystead TA. Smooth muscle phosphatase is regulated in vivo by exclusion of phosphorylation of threonine 696 of MYPT1 by phosphorylation of Serine 695 in response to cyclic nucleotides. J Biol Chem. 2004 Aug 13;279(33):34496-504. Epub 2004 Jun 11. PMID:15194681 doi:10.1074/jbc.M405957200
- ↑ Antl M, von Bruhl ML, Eiglsperger C, Werner M, Konrad I, Kocher T, Wilm M, Hofmann F, Massberg S, Schlossmann J. IRAG mediates NO/cGMP-dependent inhibition of platelet aggregation and thrombus formation. Blood. 2007 Jan 15;109(2):552-9. Epub 2006 Sep 21. PMID:16990611 doi:blood-2005-10-026294
- ↑ Yuasa K, Matsuda T, Tsuji A. Functional regulation of transient receptor potential canonical 7 by cGMP-dependent protein kinase Ialpha. Cell Signal. 2011 Jul;23(7):1179-87. doi: 10.1016/j.cellsig.2011.03.005. Epub, 2011 Mar 21. PMID:21402151 doi:10.1016/j.cellsig.2011.03.005
- ↑ Qin L, Sankaran B, Aminzai S, Casteel D, Kim C. Structural basis for selective inhibition of human PKG Ialpha by the balanol-like compound N46. J Biol Chem. 2018 May 16. pii: RA118.002427. doi: 10.1074/jbc.RA118.002427. PMID:29769318 doi:https://dx.doi.org/10.1074/jbc.RA118.002427
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