Journal
NATURE
Volume 469, Issue 7329, Pages 175-180Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature09648
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Funding
- National Institutes of Health [NS028471, GM083118, GM56169, P01 GM75913, P60DK-20572]
- Mathers Foundation
- Lundbeck Foundation
- University of Michigan
- Fund for Scientific Research of Flanders (FWO-Vlaanderen)
- Institute for the encouragement of Scientific Research and Innovation of Brussels (ISRIB)
- Lundbeck Foundation [R37-2009-3457] Funding Source: researchfish
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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.
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