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• W2471992026 abstract "Stabilization of an active and inactive conformation of the β2-adrenergic receptor by allosteric nanobodies reveals differential ligand-dependent regulation of receptor states to control G-protein-coupled receptor activation. In this manuscript, the authors studied how a positive allosteric nanobody (Nb80) and a newly discovered negative allosteric nanobody (Nb60) alter the structure of the β2-adrenergic receptor (β2AR). Their data support a three-state model for receptor activation in this important G-protein-coupled receptor, rather than a simple inactive–active two-state model. They also find that full agonists primarily stabilize the active Nb80-stabilized receptor state (while having negligible effects on the inactive Nb60-bound state), but partial agonists appear to regulate multiple receptor states to control receptor activation. G-protein-coupled receptors (GPCRs) modulate many physiological processes by transducing a variety of extracellular cues into intracellular responses. Ligand binding to an extracellular orthosteric pocket propagates conformational change to the receptor cytosolic region to promote binding and activation of downstream signalling effectors such as G proteins and β-arrestins. It is well known that different agonists can share the same binding pocket but evoke unique receptor conformations leading to a wide range of downstream responses (‘efficacy’)1. Furthermore, increasing biophysical evidence, primarily using the β2-adrenergic receptor (β2AR) as a model system, supports the existence of multiple active and inactive conformational states2,3,4,5. However, how agonists with varying efficacy modulate these receptor states to initiate cellular responses is not well understood. Here we report stabilization of two distinct β2AR conformations using single domain camelid antibodies (nanobodies)—a previously described positive allosteric nanobody (Nb80)6,7 and a newly identified negative allosteric nanobody (Nb60). We show that Nb60 stabilizes a previously unappreciated low-affinity receptor state which corresponds to one of two inactive receptor conformations as delineated by X-ray crystallography and NMR spectroscopy. We find that the agonist isoprenaline has a 15,000-fold higher affinity for β2AR in the presence of Nb80 compared to the affinity of isoprenaline for β2AR in the presence of Nb60, highlighting the full allosteric range of a GPCR. Assessing the binding of 17 ligands of varying efficacy to the β2AR in the absence and presence of Nb60 or Nb80 reveals large ligand-specific effects that can only be explained using an allosteric model which assumes equilibrium amongst at least three receptor states. Agonists generally exert efficacy by stabilizing the active Nb80-stabilized receptor state (R80). In contrast, for a number of partial agonists, both stabilization of R80 and destabilization of the inactive, Nb60-bound state (R60) contribute to their ability to modulate receptor activation. These data demonstrate that ligands can initiate a wide range of cellular responses by differentially stabilizing multiple receptor states." @default.
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• W2471992026 date "2016-07-01" @default.
• W2471992026 modified "2023-10-17" @default.
• W2471992026 title "Allosteric nanobodies reveal the dynamic range and diverse mechanisms of G-protein-coupled receptor activation" @default.
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• W2471992026 doi "https://doi.org/10.1038/nature18636" @default.
• W2471992026 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4961583" @default.
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