Title | Structure of a nanobody-stabilized active state of the β(2) adrenoceptor. |
Publication Type | Journal Article |
Year of Publication | 2011 |
Authors | Rasmussen, S. G. F., H-J. Choi, J. Jose Fung, E. Pardon, P. Casarosa, P. Seok Chae, B. T. Devree, D. M. Rosenbaum, F. Sun Thian, T. Sun Kobilka, A. Schnapp, I. Konetzki, R. K. Sunahara, S. H. Gellman, A. Pautsch, J. Steyaert, W. I. Weis, and B. K. Kobilka |
Journal | Nature |
Volume | 469 |
Issue | 7329 |
Pagination | 175-80 |
Date Published | 2011 Jan 13 |
ISSN | 1476-4687 |
Keywords | Adrenergic 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. |
DOI | 10.1038/nature09648 |
Alternate Journal | Nature |
PubMed ID | 21228869 |
PubMed Central ID | PMC3058308 |
Grant List | GM083118 / 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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