Brian Kobilka's group at Stanford and collaborators determined structures of two different muscarinic acetylcholine receptors (mAChR) from a GPCR subfamily involved in regulation of a wide variety of physiological processes such as smooth muscle contraction, endocrine and exocrine secretion, thermal homeostasis, and certain central nervous system functions. In addition to their important physiological roles, mAChRs also exhibit unique pharmacological properties that make the family an important model system in studies of GPCR allostery. The five mAChR subtypes (M1-M5) have high sequence identity, but exhibit pronounced differences in G protein coupling preference and the physiological responses they mediate. The high sequence identity has made it difficult to develop drugs that are highly selective for individual mAChR subtypes. Crystal structures of M2 and M3 muscarinic receptors allow the first structural comparison of two members of a mammalian GPCR subfamily that display different G-protein coupling selectivities (Haga et al., 2012; Kruse et al., 2012). These structures also provide insights into the challenges of developing subtype-selective ligands for muscarinic receptors and their propensity for allosteric regulation.
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Figure: A surface view of the M3 muscarinic receptor shows the very narrow binding pore with details of binding interactions with the antagonist tiotropium (yellow) at the upper right. |
Citation:
Haga, K, Kruse, AC, Asada, H, Yurugi-Kobayashi, T, Shiroishi, M, Zhang, C,
Weis, WI, Okada, T, Kobilka, BK, Haga, T, Kobayashi, T. Structure of the
human M2 muscarinic acetylcholine receptor bound to an antagonist, Nature
482, 547-551 (2012). Kruse, AC, Hu, J, Pan, AC, Arlow, DH, Rosenbaum, DM,
Rosemond, E, Green, HF, Liu, T, Chae, PS, Dror, RO, Shaw, DE, Weis, WI, Wess,
J, Kobilka, BK. Structure and dynamics of the M3 muscarinic acetylcholine
receptor, Nature 482, 552-556 (2012).
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