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Title: Crystal structures of the M1 and M4 muscarinic acetylcholine receptors

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. In this paper, 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. Finally, 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.
Authors:
 [1] ;  [2] ;  [2] ;  [1] ;  [1] ;  [3] ;  [4] ;  [5] ;  [6] ;  [2] ;  [2] ;  [1] ;  [7] ;  [1]
  1. Monash Univ., Melbourne, VIC (Australia). Monash Inst. of Pharmaceutical Sciences. Drug Discovery Biology. Dept. of Pharmacology
  2. ConfometRx, Santa Clara, CA (United States)
  3. Eli Lilly, Indianapolis, IN (United States). Dept. of Neuroscience
  4. Eli Lilly, Indianapolis, IN (United States). Dept. of Computational Chemistry and Chemoinformatics
  5. Eli Lilly, Windlesham (United Kingdom). Dept. of Computational Chemistry and Chemoinformatics
  6. Stanford Univ., CA (United States). School of Medicine. Dept. of Molecular and Cellular Physiology. Dept. of Structural Biology
  7. ConfometRx, Santa Clara, CA (United States); Stanford Univ., CA (United States). School of Medicine. Dept. of Molecular and Cellular Physiology
Publication Date:
OSTI Identifier:
1248385
Grant/Contract Number:
W-31-109-ENG-38; Y1-CO-1020; Y1-GM-1104; APP1055134
Type:
Accepted Manuscript
Journal Name:
Nature (London)
Additional Journal Information:
Journal Name: Nature (London); Journal Volume: 531; Journal Issue: 7594; Journal ID: ISSN 0028-0836
Publisher:
Nature Publishing Group
Research Org:
Stanford Univ., CA (United States); Monash Univ., Melbourne, VIC (Australia)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Inst. of Health (NIH) (United States); Lilly Research Award Program (United States); Mathers Foundation (United States); National Health and Medical Research Council (NHMRC) (Australia)
Contributing Orgs:
ConfometRx, Santa Clara, CA (United States); Eli Lilly, Indianapolis, IN (United States); Eli Lilly, Windlesham (United Kingdom)
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; X-ray crystallography; G protein-coupled receptors