19353579

pubmed:Citation

4

The 2.4 A crystal structure of the beta(2)-adrenergic receptor (beta(2)AR) in complex with the high-affinity inverse agonist (-)-carazolol provides a detailed structural framework for the analysis of ligand recognition by adrenergic receptors. Insights into agonist binding and the corresponding conformational changes triggering G-protein coupled receptor (GPCR) activation mechanism are of special interest. Here we show that while the carazolol pocket captured in the beta(2)AR crystal structure accommodates (-)-isoproterenol and other agonists without steric clashes, a finite movement of the flexible extracellular part of TM-V helix (TM-Ve) obtained by receptor optimization in the presence of docked ligand can further improve the calculated binding affinities for agonist compounds. Tilting of TM-Ve towards the receptor axis provides a more complete description of polar receptor-ligand interactions for full and partial agonists, by enabling optimal engagement of agonists with two experimentally identified anchor sites, formed by Asp113/Asn312 and Ser203/Ser204/Ser207 side chains. Further, receptor models incorporating a flexible TM-V backbone allow reliable prediction of binding affinities for a set of diverse ligands, suggesting potential utility of this approach to design of effective and subtype-specific agonists for adrenergic receptors. Systematic differences in capacity of partial, full and inverse agonists to induce TM-V helix tilt in the beta(2)AR model suggest potential role of TM-V as a conformational "rheostat" involved in the whole spectrum of beta(2)AR responses to small molecule signals.

http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-10510435, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-10617140, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-10617695, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-10810153, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-10926528, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-10964911, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-11053148, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-11356949, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-11665562, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-11934812, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-12167654, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-12435811, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-1358663, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-14559905, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-15102946, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-15266027, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-15655528, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-15817484, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-16509586, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-1678850, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-16789897, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-17188232, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-17438264, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-17513420, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-17629961, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-17962519, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-17962520, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-18059316, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-18382464, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-18547522, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-18594507, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-18680279, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-2547766, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-2899076, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-6113900, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-8101966, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-8289329, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-8626427, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-8799191, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-8845371, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-9249239, http://linkedlifedata.com/resource/pubmed/commentcorrection/19353579-9443940

http://linkedlifedata.com/resource/pubmed/journal/9004580

http://linkedlifedata.com/resource/pubmed/chemical/Adrenergic beta-2 Receptor Agonists, http://linkedlifedata.com/resource/pubmed/chemical/Adrenergic beta-2 Receptor..., http://linkedlifedata.com/resource/pubmed/chemical/Albuterol, http://linkedlifedata.com/resource/pubmed/chemical/Amphetamines, http://linkedlifedata.com/resource/pubmed/chemical/Catechols, http://linkedlifedata.com/resource/pubmed/chemical/Hydroxyquinolines, http://linkedlifedata.com/resource/pubmed/chemical/Isoproterenol, http://linkedlifedata.com/resource/pubmed/chemical/Ligands, http://linkedlifedata.com/resource/pubmed/chemical/Propanolamines, http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Adrenergic, beta-2, http://linkedlifedata.com/resource/pubmed/chemical/carazolol, http://linkedlifedata.com/resource/pubmed/chemical/carmoterol, http://linkedlifedata.com/resource/pubmed/chemical/catechol

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(c) 2009 John Wiley & Sons, Ltd.

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2011-5-24