title: Structure of a nanobody-stabilized active state of the β(2) adrenoceptor.
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 β(2) adrenergic receptor (β(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 β(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.
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, California 94305, USA.
authors.forename: Søren G F
authors.initials: SG
authors.lastname: Rasmussen
authors.forename: Hee-Jung
authors.initials: HJ
authors.lastname: Choi
authors.forename: Juan Jose
authors.initials: JJ
authors.lastname: Fung
authors.forename: Els
authors.initials: E
authors.lastname: Pardon
authors.forename: Paola
authors.initials: P
authors.lastname: Casarosa
authors.forename: Pil Seok
authors.initials: PS
authors.lastname: Chae
authors.forename: Brian T
authors.initials: BT
authors.lastname: Devree
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Rosenbaum
authors.forename: Foon Sun
authors.initials: FS
authors.lastname: Thian
authors.forename: Tong Sun
authors.initials: TS
authors.lastname: Kobilka
authors.forename: Andreas
authors.initials: A
authors.lastname: Schnapp
authors.forename: Ingo
authors.initials: I
authors.lastname: Konetzki
authors.forename: Roger K
authors.initials: RK
authors.lastname: Sunahara
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Gellman
authors.forename: Alexander
authors.initials: A
authors.lastname: Pautsch
authors.forename: Jan
authors.initials: J
authors.lastname: Steyaert
authors.forename: William I
authors.initials: WI
authors.lastname: Weis
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kobilka
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D002161:Camelids, New World; D018360:Crystallography, X-Ray; D054314:Drug Inverse Agonism; D006801:Humans; D007128:Immunoglobulin Fragments / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D009068:Movement / Q000187:drug effects; D049329:Nanostructures / Q000737:chemistry*; D055355:Opsins / Q000819:agonists / Q000737:chemistry / Q000378:metabolism; D011412:Propanolamines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011487:Protein Conformation / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry* / Q000378:metabolism*; D014764:Viral Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D007128:Immunoglobulin Fragments; D008024:Ligands; D055355:Opsins; D011412:Propanolamines; D018343:Receptors, Adrenergic, beta-2; D014764:Viral Proteins; C068293:gene 5 protein, Enterobacteria phage T4; C014382:carazolol