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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adrenergic beta-2 Receptor Agonists / chemistry*
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Adrenergic beta-2 Receptor Agonists / immunology
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Adrenergic beta-2 Receptor Agonists / metabolism
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Adrenergic beta-2 Receptor Agonists / pharmacology*
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Animals
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Binding Sites
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Camelids, New World
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Crystallography, X-Ray
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Drug Inverse Agonism
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Humans
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Immunoglobulin Fragments / chemistry*
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Immunoglobulin Fragments / immunology*
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Immunoglobulin Fragments / metabolism
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Immunoglobulin Fragments / pharmacology
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Ligands
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Models, Molecular
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Movement / drug effects
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Nanostructures / chemistry*
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Opsins / agonists
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Opsins / chemistry
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Opsins / metabolism
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Propanolamines / chemistry
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Propanolamines / metabolism
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Propanolamines / pharmacology
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Protein Conformation / drug effects
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Protein Stability / drug effects
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Receptors, Adrenergic, beta-2 / chemistry*
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Receptors, Adrenergic, beta-2 / metabolism*
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Viral Proteins / chemistry
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Viral Proteins / metabolism
Substances
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Adrenergic beta-2 Receptor Agonists
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Immunoglobulin Fragments
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Ligands
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Opsins
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Propanolamines
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Receptors, Adrenergic, beta-2
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Viral Proteins
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gene 5 protein, Enterobacteria phage T4
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carazolol