Crystal structures of the M1 and M4 muscarinic acetylcholine receptors

• Published in: Nature (London) 2016-03, Vol.531 (7594), p.335-340
• Main Authors: Thal, David M., Sun, Bingfa, Feng, Dan, Nawaratne, Vindhya, Leach, Katie, Felder, Christian C., Bures, Mark G., Evans, David A., Weis, William I., Bachhawat, Priti, Kobilka, Tong Sun, Sexton, Patrick M., Kobilka, Brian K., Christopoulos, Arthur
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; 631/535/1266; 631/92/612/194; Acetylcholine - metabolism; Allosteric Regulation - drug effects; Allosteric Site - drug effects; Alzheimer Disease; Alzheimer's disease; Analysis; BASIC BIOLOGICAL SCIENCES; Binding sites; Crystal structure; Crystallization; Crystallography, X-Ray; Crystals; Drug Inverse Agonism; G protein-coupled receptors; Humanities and Social Sciences; Humans; Mental disorders; Models, Molecular; multidisciplinary; Muscarinic receptors; Mutagenesis; Mutation; Nervous system; Neurotransmitters; Nicotinic Acids - metabolism; Nicotinic Acids - pharmacology; Properties; Proteins; Receptor, Muscarinic M1 - chemistry; Receptor, Muscarinic M1 - metabolism; Receptor, Muscarinic M4 - chemistry; Receptor, Muscarinic M4 - metabolism; Schizophrenia; Science; Static Electricity; Structure; Substrate Specificity; Surface Properties; Thiophenes - metabolism; Thiophenes - pharmacology; Tiotropium Bromide - pharmacology; X-ray crystallography
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature17188

Muscarinic M1–M5 acetylcholine receptors are G-protein-coupled receptors that regulate many vital functions of the central and peripheral nervous systems. In particular, the M1 and M4 receptor subtypes have emerged as attractive drug targets for treatments of neurological disorders, such as Alzheimer’s disease and schizophrenia, but the high conservation of the acetylcholine-binding pocket has spurred current research into targeting allosteric sites on these receptors. Here we report the crystal structures of the M1 and M4 muscarinic receptors bound to the inverse agonist, tiotropium. Comparison of these structures with each other, as well as with the previously reported M2 and M3 receptor structures, reveals differences in the orthosteric and allosteric binding sites that contribute to a role in drug selectivity at this important receptor family. We also report identification of a cluster of residues that form a network linking the orthosteric and allosteric sites of the M4 receptor, which provides new insight into how allosteric modulation may be transmitted between the two spatially distinct domains. X-ray crystal structures of the M1 and M4 muscarinic acetylcholine receptors, revealing differences in the orthosteric and allosteric binding sites that help to explain the subtype selectivity of drugs targeting this family of receptors. M1 and M4 muscarinic acetylcholine receptor structures Arthur Christopoulos and colleagues present the first X-ray crystal structures of the M1 and M4 muscarinic acetylcholine receptors, G-protein-coupled receptors (GPCRs) that regulate many vital functions of the central and peripheral nervous systems. The structures reveal differences in the orthosteric and allosteric binding sites that help to explain the subtype selectivity of drugs targeting this family of receptors. The M1 and M4 receptor subtypes are potential drug targets for treatments of neurological disorders, such as Alzheimer's disease and schizophrenia.