Analysis of full and partial agonists binding to beta2-adrenergic receptor suggests a role of transmembrane helix V in agonist-specific conformational changes.
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.
Katritch
Vsevolod
V
Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. katritch@scripps.edu
Reynolds
Kimberly A
KA
Cherezov
Vadim
V
Hanson
Michael A
MA
Roth
Christopher B
CB
Yeager
Mark
M
Abagyan
Ruben
R
D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000420:Albuterol / Q000737:chemistry / Q000494:pharmacology; D000662:Amphetamines / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002396:Catechols / Q000737:chemistry / Q000494:pharmacology; D004298:Dopamine / Q000737:chemistry / Q000494:pharmacology; D054333:Drug Partial Agonism; D006912:Hydroxyquinolines / Q000737:chemistry / Q000494:pharmacology; D007545:Isoproterenol / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D018583:Pliability / Q000187:drug effects; D011412:Propanolamines / Q000737:chemistry / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000662:Amphetamines; D002396:Catechols; D006912:Hydroxyquinolines; D008024:Ligands; D011412:Propanolamines; D018343:Receptors, Adrenergic, beta-2; C014382:carazolol; C074413:carmoterol; D007545:Isoproterenol; C034221:catechol; D000420:Albuterol; D004298:Dopamine