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5j48

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Revision as of 12:53, 6 November 2017

PKG I's Carboyl Terminal Cyclic Nucleotide Binding Domain (CNB-B) in a complex with 8-pCPT-cGMP

Structural highlights

5j48 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , ,
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

Cyclic GMP analogs, 8-Br, 8-pCPT, and PET-cGMP, have been widely used for characterizing cellular functions of cGMP-dependent protein kinase (PKG) I and II isotypes. However, interpreting results obtained using these analogs has been difficult due to their low isotype specificity. Additionally, each isotype has two binding sites with different cGMP affinities and analog selectivities, making understanding the molecular basis for isotype specificity of these compounds even more challenging. To determine isotype specificity of cGMP analogs and their structural basis, we generated the full-length regulatory domains of PKG I and II isotypes with each binding site disabled, determined their affinities for these analogs, and obtained cocrystal structures of both isotypes bound with cGMP analogs. Our affinity and activation measurements show that PET-cGMP is most selective for PKG I, whereas 8-pCPT-cGMP is most selective for PKG II. Our structures of cyclic nucleotide binding (CNB) domains reveal that the B site of PKG I is more open and forms a unique pi/pi interaction through Arg285 at beta4 with the PET moiety, whereas the A site of PKG II has a larger beta5/beta6 pocket that can better accommodate the bulky 8-pCPT moiety. Our structural and functional results explain the selectivity of these analogs for each PKG isotype and provide a starting point for the rational design of isotype selective activators.

Structural Basis of Analog Specificity in PKG I and II.,Campbell JC, Henning P, Franz E, Sankaran B, Herberg FW, Kim C ACS Chem Biol. 2017 Aug 22. doi: 10.1021/acschembio.7b00369. PMID:28793191^[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
↑ Campbell JC, Henning P, Franz E, Sankaran B, Herberg FW, Kim C. Structural Basis of Analog Specificity in PKG I and II. ACS Chem Biol. 2017 Aug 22. doi: 10.1021/acschembio.7b00369. PMID:28793191 doi:http://dx.doi.org/10.1021/acschembio.7b00369

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5j48"

@@ Line 3: / Line 3: @@
 <StructureSection load='5j48' size='340' side='right' caption='[[5j48]], [[Resolution|resolution]] 1.49&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5j48]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5J48 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5J48 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5j48]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5J48 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5J48 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6FW:2-AMINO-8-[(4-CHLOROPHENYL)SULFANYL]-9-[(2S,4AR,6R,7R,7AS)-2,7-DIHYDROXY-2-OXOTETRAHYDRO-2H,4H-2LAMBDA~5~-FURO[3,2-D][1,3,2]DIOXAPHOSPHININ-6-YL]-3,9-DIHYDRO-6H-PURIN-6-ONE'>6FW</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PRKG1, PRKG1B, PRKGR1A, PRKGR1B ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.12 2.7.11.12] </span></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5j48 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j48 OCA], [http://pdbe.org/5j48 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5j48 RCSB], [http://www.ebi.ac.uk/pdbsum/5j48 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5j48 ProSAT]</span></td></tr>
@@ Line 23: / Line 24: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Transferase]]
 [[Category: Campbell, J C]]

5j48

From Proteopedia

Revision as of 12:53, 6 November 2017

PKG I's Carboyl Terminal Cyclic Nucleotide Binding Domain (CNB-B) in a complex with 8-pCPT-cGMP

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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