Structure of a nanobody-stabilized active state of the b2 adrenoceptor

Soren 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

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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 beta(2) adrenergic receptor (beta(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 beta(2)AR structure reveals subtle changes in the binding pocket; however, these small changes are associated with an 11 angstrom 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)175-180
Number of pages5
Issue number7329
Publication statusPublished - 13 Apr 2011




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