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6c2y

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Revision as of 08:32, 2 May 2018

Human GRK2 in complex with Gbetagamma subunits and CCG257142

Structural highlights

6c2y is a 3 chain structure with sequence from Bovin and Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	GRK2, ADRBK1, BARK, BARK1 (HUMAN), GNB1 (BOVIN), GNG2 (BOVIN)
Activity:	[Beta-adrenergic-receptor_kinase [Beta-adrenergic-receptor] kinase], with EC number 2.7.11.15
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[ARBK1_HUMAN] Specifically phosphorylates the agonist-occupied form of the beta-adrenergic and closely related receptors, probably inducing a desensitization of them. Key regulator of LPAR1 signaling. Competes with RALA for binding to LPAR1 thus affecting the signaling properties of the receptor. Desensitizes LPAR1 and LPAR2 in a phosphorylation-independent manner.^[1] [GBG2_BOVIN] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction. [GBB1_BOVIN] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.

Publication Abstract from PubMed

G protein-coupled receptor (GPCR) kinases (GRKs) regulate the desensitization and internalization of GPCRs. Two of these, GRK2 and GRK5, are upregulated in heart failure and are promising targets for heart failure treatment. Although there have been several reports of potent and selective inhibitors of GRK2 there are few for GRK5. Herein, we describe a ligand docking approach utilizing the crystal structures of the GRK2-Gbetagamma.GSK180736A and GRK5.CCG215022 complexes to search for amide substituents predicted to confer GRK2 and/or GRK5 potency and selectivity. From this campaign, we successfully generated two new potent GRK5 inhibitors, although neither exhibited selectivity over GRK2.

Utilizing a structure-based docking approach to develop potent G protein-coupled receptor kinase (GRK) 2 and 5 inhibitors.,Waldschmidt HV, Bouley R, Kirchhoff PD, Lee P, Tesmer JJG, Larsen SD Bioorg Med Chem Lett. 2018 May 15;28(9):1507-1515. doi:, 10.1016/j.bmcl.2018.03.082. Epub 2018 Mar 30. PMID:29627263^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Aziziyeh AI, Li TT, Pape C, Pampillo M, Chidiac P, Possmayer F, Babwah AV, Bhattacharya M. Dual regulation of lysophosphatidic acid (LPA1) receptor signalling by Ral and GRK. Cell Signal. 2009 Jul;21(7):1207-17. doi: 10.1016/j.cellsig.2009.03.011. Epub, 2009 Mar 21. PMID:19306925 doi:10.1016/j.cellsig.2009.03.011
↑ Waldschmidt HV, Bouley R, Kirchhoff PD, Lee P, Tesmer JJG, Larsen SD. Utilizing a structure-based docking approach to develop potent G protein-coupled receptor kinase (GRK) 2 and 5 inhibitors. Bioorg Med Chem Lett. 2018 May 15;28(9):1507-1515. doi:, 10.1016/j.bmcl.2018.03.082. Epub 2018 Mar 30. PMID:29627263 doi:http://dx.doi.org/10.1016/j.bmcl.2018.03.082

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/6c2y"

Categories: Bovin | Human | Bouley, R | Tesmer, J J.G | Transferase-signaling protein complex

@@ Line 3: / Line 3: @@
 <StructureSection load='6c2y' size='340' side='right' caption='[[6c2y]], [[Resolution|resolution]] 2.74&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6c2y]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6C2Y OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6C2Y FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6c2y]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Bovin Bovin] and [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6C2Y OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6C2Y FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EJS:(4R,5R,6S)-4-[4-fluoro-3-({[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]methyl}carbamoyl)phenyl]-N-(2H-indazol-5-yl)-6-methyl-2-oxohexahydropyrimidine-5-carboxamide'>EJS</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GRK2, ADRBK1, BARK, BARK1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), GNB1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9913 BOVIN]), GNG2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9913 BOVIN])</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/[Beta-adrenergic-receptor]_kinase [Beta-adrenergic-receptor] kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.15 2.7.11.15] </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=6c2y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6c2y OCA], [http://pdbe.org/6c2y PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6c2y RCSB], [http://www.ebi.ac.uk/pdbsum/6c2y PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6c2y ProSAT]</span></td></tr>
@@ Line 23: / Line 24: @@
 __TOC__
 </StructureSection>
+[[Category: Bovin]]
+[[Category: Human]]
 [[Category: Bouley, R]]
 [[Category: Tesmer, J J.G]]
 [[Category: Transferase-signaling protein complex]]

6c2y

From Proteopedia

Revision as of 08:32, 2 May 2018

Human GRK2 in complex with Gbetagamma subunits and CCG257142

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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