Research ArticleGPCR SIGNALING

Mutations in the NPxxY motif stabilize pharmacologically distinct conformational states of the α1B- and β2-adrenoceptors

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Science Signaling  12 Mar 2019:
Vol. 12, Issue 572, eaas9485
DOI: 10.1126/scisignal.aas9485

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Pharmacological heterogeneity in GPCRs

G protein–coupled receptors (GPCRs) share a common overall structure that switches between inactive and active conformations, with the latter being stabilized by ligand binding. Ragnarsson et al. investigated the role of a switch formed by hydrogen bonds between the NPxxY motif in transmembrane helix 7 (TMH7) and a tyrosine residue in TMH5 in activation of the α1B- and β2-adrenoceptors (ARs). Mutating the switch stabilized the inactive receptor conformations, resulting in reduced signaling. Although the mutations reduced the agonist affinity of the β2-AR without affecting signaling efficacy, they enhanced the agonist affinity and reduced the signaling efficacy of the α1B-AR. These findings show that inactive conformations of individual GPCRs have different pharmacological properties, which may help with designing new drugs or improving the efficacy and reducing the side effects of existing drugs.