Epitopes described in "Structure of a nanobody-stabilized active state of the β(2) adrenoceptor."

Article Authors:Søren G F Rasmussen; Hee-Jung Choi; Juan Jose Fung; Els Pardon; Paola Casarosa; Pil Seok Chae; Brian T Devree; Daniel M Rosenbaum; Foon Sun Thian; Tong Sun Kobilka; Andreas Schnapp; Ingo Konetzki; Roger K Sunahara; Samuel H Gellman; Alexander Pautsch; Jan Steyaert; William I Weis; Brian K Kobilka
Article Title:Structure of a nanobody-stabilized active state of the β(2) adrenoceptor.
Reference Detail
Reference ID:1022177
Abstract:G protein coupled receptors (GPCRs) exhibit a spectrum of functional behaviours in response to natural and synthetic ligands. Recent crystal structures provide insights into inactive states of several GPCRs. Efforts to obtain an agonist-bound active-state GPCR structure have proven difficult due to the inherent instability of this state in the absence of a G protein. We generated a camelid antibody fragment (nanobody) to the human (2) adrenergic receptor ((2)AR) that exhibits G protein-like behaviour, and obtained an agonist-bound, active-state crystal structure of the receptor-nanobody complex. Comparison with the inactive (2)AR structure reveals subtle changes in the binding pocket; however, these small changes are associated with an 11 Å outward movement of the cytoplasmic end of transmembrane segment 6, and rearrangements of transmembrane segments 5 and 7 that are remarkably similar to those observed in opsin, an active form of rhodopsin. This structure provides insights into the process of agonist binding and activation.
Affiliations:Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, California 94305, USA.
Reference Type:Literature
PubMed ID:21228869
Journal Volume:469
Article Pages:175-80
Journal ISSN:1476-4687
Article Chemical List:Adrenergic beta-2 Receptor Agonists;Immunoglobulin Fragments;Ligands;Opsins;Propanolamines;Receptors, Adrenergic, beta-2;Viral Proteins;gene 5 protein, Enterobacteria phage T4;carazolol
Article MeSH List:Adrenergic beta-2 Receptor Agonists(chemistry; immunology; metabolism; pharmacology); Animals; Binding Sites; Camelids, New World; Crystallography, X-Ray; Drug Inverse Agonism; Humans; Immunoglobulin Fragments(chemistry; immunology; metabolism; pharmacology); Ligands; Models, Molecular; Movement(drug effects); Nanostructures(chemistry); Opsins(agonists; chemistry; metabolism); Propanolamines(chemistry; metabolism; pharmacology); Protein Conformation(drug effects); Protein Stability(drug effects); Receptors, Adrenergic, beta-2(chemistry; metabolism); Viral Proteins(chemistry; metabolism)
Curation Last Updated:2015-06-07 20:04:28