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4l9i

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Revision as of 12:38, 5 August 2016

Bovine G Protein Coupled Receptor Kinase 1 in Complex with Paroxetine

Structural highlights

4l9i is a 2 chain structure with sequence from Bovin. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	3c50, 3v5w, 4mk0
Gene:	GRK1, RHOK (BOVIN)
Activity:	Rhodopsin kinase, with EC number 2.7.11.14
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[RK_BOVIN] Retina-specific kinase involved in the signal turnoff via phosphorylation of rhodopsin (RHO), the G protein- coupled receptor that initiates the phototransduction cascade. This rapid desensitization is essential for scotopic vision and permits rapid adaptation to changes in illumination (By similarity).

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^[1]

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

References

↑ 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/4l9i"

@@ Line 1: / Line 1: @@
 ==Bovine G Protein Coupled Receptor Kinase 1 in Complex with Paroxetine==
 <StructureSection load='4l9i' size='340' side='right' caption='[[4l9i]], [[Resolution|resolution]] 2.32&Aring;' scene=''>
@@ Line 7: / Line 8: @@
 <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GRK1, RHOK ([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/Rhodopsin_kinase Rhodopsin kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.14 2.7.11.14] </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=4l9i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4l9i OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4l9i RCSB], [http://www.ebi.ac.uk/pdbsum/4l9i 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=4l9i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4l9i OCA], [http://pdbe.org/4l9i PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4l9i RCSB], [http://www.ebi.ac.uk/pdbsum/4l9i PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4l9i 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 4l9i" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Rhodopsin kinase|Rhodopsin kinase]]
 == References ==
 <references/>

4l9i

From Proteopedia

Revision as of 12:38, 5 August 2016

Bovine G Protein Coupled Receptor Kinase 1 in Complex with Paroxetine

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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