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

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 G(q/11) family, whereas M2R and M4R couple to the G(i/o) family. Here, we present and compare the cryo-electron microscopy structures of M1R in complex with G(11) and M2R in complex with G(oA). The M1R-G(11) 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.