Structure of a nanobody-stabilized active state of the β2 adrenoceptor

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

Research output: Contribution to journalArticleResearchpeer-review

1129 Citations (Scopus)

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 β2 adrenergic receptor (β2 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 β2 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.

Original languageEnglish
Pages (from-to)175-181
Number of pages7
JournalNature
Volume469
Issue number7329
DOIs
Publication statusPublished - 13 Jan 2011
Externally publishedYes

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