Structural Biology

Many Ways of Conforming

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Science  02 Sep 2011:
Vol. 333, Issue 6047, pp. 1201
DOI: 10.1126/science.333.6047.1201-b

G protein–coupled receptors (GPCRs) are activated by numerous extracellular stimuli and in turn activate diverse downstream pathways. Rather than ligand-dependent shifting of receptor equilibrium between single active and inactive conformations, with the relative activation of a particular pathway depending on the degree of coupling to that pathway, recent evidence suggests that multiple receptor conformations signal different pathways selectively. For example, the β2-adrenergic receptor (β2AR) signals through both G proteins and β-arrestins, and “biased ligands” were shown to selectively activate only a subset of pathways. Crystal structures have provided insight into GPCR function and, in particular, Rasmussen et al. reported a structure of agonist-occupied β2AR bound to a G protein that provides a high-resolution view of conformational changes associated with activation. Crystal structures, however, cannot capture the full dynamics of GPCRs. Kahsai et al. used a quantitative mass spectroscopy approach and focused on the reactivity of specific residues to investigate the effects of nine functionally distinct ligands on β2AR conformation. Although some ligands induced reactivity that resembled classical receptor agonism, other ligands showed induced patterns suggestive of multiple ligand-specific conformations. Discovery of structural elements associated with specific signaling pathways could lead to new strategies in therapeutic development.

Nature 10.1038/nature10361 (2011); Nat. Chem.Biol. 7, 10.1038/NCHEMBIO.634 (2011).

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