Structure of a nanobody-stabilized active state of the β(2) adrenoceptor.

TitleStructure of a nanobody-stabilized active state of the β(2) adrenoceptor.
Publication TypeJournal Article
Year of Publication2011
AuthorsRasmussen, S. G. F., Choi H-J., Fung J. Jose, Pardon E., Casarosa P., Chae P. Seok, Devree B. T., Rosenbaum D. M., Thian F. Sun, Kobilka T. Sun, Schnapp A., Konetzki I., Sunahara R. K., Gellman S. H., Pautsch A., Steyaert J., Weis W. I., and Kobilka B. K.
JournalNature
Volume469
Issue7329
Pagination175-80
Date Published2011 Jan 13
ISSN1476-4687
KeywordsAdrenergic beta-2 Receptor Agonists, Animals, Binding Sites, Camelids, New World, Crystallography, X-Ray, Drug Inverse Agonism, Humans, Immunoglobulin Fragments, Ligands, Models, Molecular, Movement, Nanostructures, Opsins, Propanolamines, Protein Conformation, Protein Stability, Receptors, Adrenergic, beta-2, Viral Proteins
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.

DOI10.1038/nature09648
Alternate JournalNature
PubMed ID21228869
PubMed Central IDPMC3058308
Grant ListGM083118 / GM / NIGMS NIH HHS / United States
GM56169 / GM / NIGMS NIH HHS / United States
NS028471 / NS / NINDS NIH HHS / United States
P01 GM75913 / GM / NIGMS NIH HHS / United States
P60DK-20572 / DK / NIDDK NIH HHS / United States
R01 GM068603 / GM / NIGMS NIH HHS / United States
R01 GM083118 / GM / NIGMS NIH HHS / United States
R01 GM083118-04 / GM / NIGMS NIH HHS / United States
R37 NS028471 / NS / NINDS NIH HHS / United States
R37 NS028471-21 / NS / NINDS NIH HHS / United States
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