5CXV

Structure of the human M1 muscarinic acetylcholine receptor bound to antagonist Tiotropium

Summary for 5CXV

• Entry DOI: 10.2210/pdb5cxv/pdb
• Descriptor: Muscarinic acetylcholine receptor M1,Endolysin,Muscarinic acetylcholine receptor M1, FLAG peptide, (1R,2R,4S,5S,7S)-7-{[hydroxy(dithiophen-2-yl)acetyl]oxy}-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0~2,4~]nonane, ... (8 entities in total)
• Functional Keywords: acetylcholine, allosteric regulation, carrier proteins, cholinergic antagonists, tiotropium receptor, muscarinic m1, gpcr, subtype selectivity, hydrolase
• Biological source: Homo sapiens (Human); More
• Cellular location: Cell membrane; Multi-pass membrane protein: P11229
• Total number of polymer chains: 2
• Total formula weight: 60846.89

Authors

Sun, B.,Feng, D.,Li, X.,Kobilka, T.S.,Kobilka, B.K. (deposition date: 2015-07-29, release date: 2016-03-09, Last modification date: 2016-03-30)

Primary citation

Thal, D.M.,Sun, B.,Feng, D.,Nawaratne, V.,Leach, K.,Felder, C.C.,Bures, M.G.,Evans, D.A.,Weis, W.I.,Bachhawat, P.,Kobilka, T.S.,Sexton, P.M.,Kobilka, B.K.,Christopoulos, A.
Crystal structures of the M1 and M4 muscarinic acetylcholine receptors.
Nature, 531:335-340, 2016

PubMed Abstract: 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.

PubMed: 26958838
DOI: 10.1038/nature17188

Experimental method

X-RAY DIFFRACTION (2.7 Å)