Research Article

Structures of the M1 and M2 muscarinic acetylcholine receptor/G-protein complexes

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Science  10 May 2019:
Vol. 364, Issue 6440, pp. 552-557
DOI: 10.1126/science.aaw5188

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G protein–coupled receptors (GPCRs) bind ligands outside the cell and trigger events inside the cell by selectively binding and activating specific G proteins. The selectivity occurs even among highly related GPCRs. For example, five subtypes of muscarinic acetylcholine receptors (M1R to M5R) play different roles in the nervous system by binding to different G proteins. Maeda et al. determined cryo–electron microscopy structures of M1R and M2R bound to their respective G proteins. A side-by-side comparison provided a molecular understanding of G protein–coupling selectivity.

Science, this issue p. 552

Abstract

Muscarinic acetylcholine receptors are G protein–coupled receptors that respond to acetylcholine and play important signaling roles in the nervous system. There are five muscarinic receptor subtypes (M1R to M5R), which, despite sharing a high degree of sequence identity in the transmembrane region, couple to different heterotrimeric GTP-binding proteins (G proteins) to transmit signals. M1R, M3R, and M5R couple to the Gq/11 family, whereas M2R and M4R couple to the Gi/o family. Here, we present and compare the cryo–electron microscopy structures of M1R in complex with G11 and M2R in complex with GoA. The M1R-G11 complex exhibits distinct features, including an extended transmembrane helix 5 and carboxyl-terminal receptor tail that interacts with G protein. Detailed analysis of these structures provides a framework for understanding the molecular determinants of G-protein coupling selectivity.

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