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4mk0

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Revision as of 09:52, 15 November 2017

Crystal structure of G protein-coupled receptor kinase 2 in complex with a a rationally designed paroxetine derivative

Structural highlights

4mk0 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:	,
Related:	3v5w, 4l9i, 1omw
Gene:	ADRBK1, BARK, BARK1, GRK2 (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

Recently we identified the serotonin reuptake inhibitor paroxetine as an inhibitor of G protein-coupled receptor kinase 2 (GRK2) that improves cardiac performance in live animals. Paroxetine exhibits up to 50-fold selectivity for GRK2 versus other GRKs. A better understanding of the molecular basis of this selectivity is important for the development of even more selective and potent small molecule therapeutics and chemical genetic probes. We first sought to understand the molecular mechanisms underlying paroxetine selectivity among GRKs. We directly measured the KD for paroxetine and assessed its mechanism of inhibition for each of the GRK subfamilies and then determined the atomic structure of its complex with GRK1, the most weakly inhibited GRK tested. Our results suggest that the selectivity of paroxetine for GRK2 largely reflects its lower affinity for adenine nucleotides. Thus, stabilization of off-pathway conformational states unique to GRK2 will likely be key for the development of even more selective inhibitors. Next, we designed a benzolactam derivative of paroxetine that has optimized interactions with the hinge of the GRK2 kinase domain. The crystal structure of this compound in complex with GRK2 confirmed the predicted interactions. Although the benzolactam derivative did not significantly alter potency of inhibition among GRKs, it exhibited 20-fold lower inhibition of serotonin reuptake. However, there was an associated increase in the potency for inhibition of other AGC kinases, suggesting that the unconventional hydrogen bond formed by the benzodioxole ring of paroxetine is better accommodated by GRKs.

Structural and functional analysis of g protein-coupled receptor kinase inhibition by paroxetine and a rationally designed analog.,Homan KT, Wu E, Wilson MW, Singh P, Larsen SD, Tesmer JJ Mol Pharmacol. 2014 Feb;85(2):237-48. doi: 10.1124/mol.113.089631. Epub 2013 Nov , 12. PMID:24220010^[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
↑ Homan KT, Wu E, Wilson MW, Singh P, Larsen SD, Tesmer JJ. Structural and functional analysis of g protein-coupled receptor kinase inhibition by paroxetine and a rationally designed analog. Mol Pharmacol. 2014 Feb;85(2):237-48. doi: 10.1124/mol.113.089631. Epub 2013 Nov , 12. PMID:24220010 doi:http://dx.doi.org/10.1124/mol.113.089631

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4mk0"

@@ Line 1: / Line 1: @@
 ==Crystal structure of G protein-coupled receptor kinase 2 in complex with a a rationally designed paroxetine derivative==
 <StructureSection load='4mk0' size='340' side='right' caption='[[4mk0]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
@@ Line 7: / Line 8: @@
 <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ADRBK1, BARK, BARK1, GRK2 ([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=4mk0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mk0 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4mk0 RCSB], [http://www.ebi.ac.uk/pdbsum/4mk0 PDBsum]</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=4mk0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mk0 OCA], [http://pdbe.org/4mk0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4mk0 RCSB], [http://www.ebi.ac.uk/pdbsum/4mk0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4mk0 ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 19: / Line 20: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4mk0" style="background-color:#fffaf0;"></div>
 ==See Also==
-*[[Guanine nucleotide-binding protein|Guanine nucleotide-binding protein]]
 *[[Transducin|Transducin]]
 == References ==

4mk0

From Proteopedia

Revision as of 09:52, 15 November 2017

Crystal structure of G protein-coupled receptor kinase 2 in complex with a a rationally designed paroxetine derivative

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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