Crystal structures of the M1 and M4 muscarinic acetylcholine receptors

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

doi:10.1038/nature17188

Crystal structures of the M₁ and M₄ muscarinic acetylcholine receptors

Journal Article · Wed Mar 09 00:00:00 EST 2016 · Nature (London)

DOI:https://doi.org/10.1038/nature17188· OSTI ID:1248385

Thal, David M. ^[1]; Sun, Bingfa ^[2]; Feng, Dan ^[2]; Nawaratne, Vindhya ^[1]; Leach, Katie ^[1]; Felder, Christian C. ^[3]; Bures, Mark G. ^[4]; Evans, David A. ^[5]; Weis, William I. ^[6]; Bachhawat, Priti ^[2]; Kobilka, Tong Sun ^[2]; Sexton, Patrick M. ^[1]; Kobilka, Brian K. ^[7]; Christopoulos, Arthur ^[1]

Monash Univ., Melbourne, VIC (Australia). Monash Inst. of Pharmaceutical Sciences. Drug Discovery Biology. Dept. of Pharmacology
ConfometRx, Santa Clara, CA (United States)
Eli Lilly, Indianapolis, IN (United States). Dept. of Neuroscience
Eli Lilly, Indianapolis, IN (United States). Dept. of Computational Chemistry and Chemoinformatics
Eli Lilly, Windlesham (United Kingdom). Dept. of Computational Chemistry and Chemoinformatics
Stanford Univ., CA (United States). School of Medicine. Dept. of Molecular and Cellular Physiology. Dept. of Structural Biology
ConfometRx, Santa Clara, CA (United States); Stanford Univ., CA (United States). School of Medicine. Dept. of Molecular and Cellular Physiology

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.

View Accepted Manuscript (DOE)

Research Organization:: Monash Univ., Melbourne, VIC (Australia); Stanford Univ., CA (United States)

Sponsoring Organization:: Lilly Research Award Program (United States); Mathers Foundation (United States); National Health and Medical Research Council (NHMRC) (Australia); National Inst. of Health (NIH) (United States); USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)

Contributing Organization:: ConfometRx, Santa Clara, CA (United States); Eli Lilly, Indianapolis, IN (United States); Eli Lilly, Windlesham (United Kingdom)

Grant/Contract Number:: W-31109-ENG-38

OSTI ID:: 1248385

Journal Information:: Nature (London), Journal Name: Nature (London) Journal Issue: 7594 Vol. 531; ISSN 0028-0836

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Copper-mediated thiol potentiation and mutagenesis-guided modeling suggest a highly conserved copper-binding motif in human OR2M3 Haag, Franziska; Ahmed, Lucky; Reiss, Krystle Cellular and Molecular Life Sciences, Vol. 77, Issue 11 https://doi.org/10.1007/s00018-019-03279-y	journal	August 2019
Novel choline analog 2-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)ethan-1-ol produces sympathoinhibition, hypotension, and antihypertensive effects Menegatti, Ricardo; Carvalho, Flávio S.; Lião, Luciano M. Naunyn-Schmiedeberg's Archives of Pharmacology, Vol. 392, Issue 9 https://doi.org/10.1007/s00210-019-01649-8	journal	May 2019
A benchmark study of loop modeling methods applied to G protein-coupled receptors Wink, Lee H.; Baker, Daniel L.; Cole, Judith A. Journal of Computer-Aided Molecular Design, Vol. 33, Issue 6 https://doi.org/10.1007/s10822-019-00196-x	journal	May 2019
Backbone cyclization of analgesic conotoxin gexiva facilitates direct folding of the ribbon isomer Wu, Xiaosa; Huang, Yen-Hua; Kaas, Quentin Toxicon, Vol. 158 https://doi.org/10.1016/j.toxicon.2018.10.146	journal	February 2019
A kinetic view of GPCR allostery and biased agonism Lane, J. Robert; May, Lauren T.; Parton, Robert G. Nature Chemical Biology, Vol. 13, Issue 9 https://doi.org/10.1038/nchembio.2431	journal	August 2017
Discovery of new GPCR ligands to illuminate new biology Roth, Bryan L.; Irwin, John J.; Shoichet, Brian K. Nature Chemical Biology, Vol. 13, Issue 11 https://doi.org/10.1038/nchembio.2490	journal	October 2017
Na+-mimicking ligands stabilize the inactive state of leukotriene B4 receptor BLT1 Hori, Tetsuya; Okuno, Toshiaki; Hirata, Kunio Nature Chemical Biology, Vol. 14, Issue 3 https://doi.org/10.1038/nchembio.2547	journal	January 2018
The molecular basis of subtype selectivity of human kinin G-protein-coupled receptors Joedicke, Lisa; Mao, Jiafei; Kuenze, Georg Nature Chemical Biology, Vol. 14, Issue 3 https://doi.org/10.1038/nchembio.2551	journal	January 2018
Development of an antibody fragment that stabilizes GPCR/G-protein complexes Maeda, Shoji; Koehl, Antoine; Matile, Hugues Nature Communications, Vol. 9, Issue 1 https://doi.org/10.1038/s41467-018-06002-w	journal	September 2018
Molecular pharmacology of metabotropic receptors targeted by neuropsychiatric drugs Roth, Bryan L. Nature Structural & Molecular Biology, Vol. 26, Issue 7 https://doi.org/10.1038/s41594-019-0252-8	journal	July 2019
Exploring a new ligand binding site of G protein-coupled receptors Chan, H. C. Stephen; Wang, Jingjing; Palczewski, Krzysztof Chemical Science, Vol. 9, Issue 31 https://doi.org/10.1039/c8sc01680a	journal	January 2018
Accelerated structure-based design of chemically diverse allosteric modulators of a muscarinic G protein-coupled receptor Miao, Yinglong; Goldfeld, Dahlia Anne; Moo, Ee Von Proceedings of the National Academy of Sciences, Vol. 113, Issue 38 https://doi.org/10.1073/pnas.1612353113	journal	September 2016
Structure-based discovery of selective positive allosteric modulators of antagonists for the M ₂ muscarinic acetylcholine receptor Korczynska, Magdalena; Clark, Mary J.; Valant, Celine Proceedings of the National Academy of Sciences, Vol. 115, Issue 10 https://doi.org/10.1073/pnas.1718037115	journal	February 2018
Allosteric modulation of β-cell M ₃ muscarinic acetylcholine receptors greatly improves glucose homeostasis in lean and obese mice Zhu, Lu; Rossi, Mario; Cohen, Amanda Proceedings of the National Academy of Sciences, Vol. 116, Issue 37 https://doi.org/10.1073/pnas.1904943116	journal	August 2019
Crystal structure of the M ₅ muscarinic acetylcholine receptor Vuckovic, Ziva; Gentry, Patrick R.; Berizzi, Alice E. Proceedings of the National Academy of Sciences, Vol. 116, Issue 51 https://doi.org/10.1073/pnas.1914446116	journal	November 2019
Backbone cyclization of analgesic conotoxin GeXIVA facilitates direct folding of the ribbon isomer Wu, Xiaosa; Huang, Yen-Hua; Kaas, Quentin Journal of Biological Chemistry, Vol. 292, Issue 41 https://doi.org/10.1074/jbc.m117.808386	journal	August 2017
Evidence of a M ₁ -muscarinic GPCR homolog in unicellular eukaryotes: featuring Acanthamoeba spp bioinformatics 3D-modelling and experimentations Baig, Abdul Mannan; Ahmad, H. R. Journal of Receptors and Signal Transduction, Vol. 37, Issue 3 https://doi.org/10.1080/10799893.2016.1217884	journal	September 2016
Crystal structure of the M ₅ muscarinic acetylcholine receptor Vuckovic, Ziva; Gentry, Patrick R.; Berizzi, Alice E. Proceedings of the National Academy of Sciences https://doi.org/10.1101/730622	journal	August 2019
Allostery at opioid receptors: modulation with small molecule ligands Livingston, Kathryn E.; Traynor, John R. British Journal of Pharmacology, Vol. 175, Issue 14 https://doi.org/10.1111/bph.13823	journal	June 2017
Novel long-acting antagonists of muscarinic ACh receptors: Muscarinic long-acting antagonists Randáková, Alena; Rudajev, Vladimír; Doležal, Vladimír British Journal of Pharmacology, Vol. 175, Issue 10 https://doi.org/10.1111/bph.14187	journal	April 2018
Positive Allosteric Modulation of the Muscarinic M ₁ Receptor Improves Efficacy of Antipsychotics in Mouse Glutamatergic Deficit Models of Behavior Choy, Kwok H. C.; Shackleford, David M.; Malone, Daniel T. Journal of Pharmacology and Experimental Therapeutics, Vol. 359, Issue 2 https://doi.org/10.1124/jpet.116.235788	journal	September 2016
Pharmacologic Evidence for a Putative Conserved Allosteric Site on Opioid Receptors Livingston, Kathryn E.; Stanczyk, M. Alexander; Burford, Neil T. Molecular Pharmacology, Vol. 93, Issue 2 https://doi.org/10.1124/mol.117.109561	journal	December 2017
Structures of the M1 and M2 muscarinic acetylcholine receptor/G-protein complexes Maeda, Shoji; Qu, Qianhui; Robertson, Michael J. Science, Vol. 364, Issue 6440 https://doi.org/10.1126/science.aaw5188	journal	May 2019
Biased M ₁ receptor–positive allosteric modulators reveal role of phospholipase D in M ₁ -dependent rodent cortical plasticity Moran, Sean P.; Xiang, Zixiu; Doyle, Catherine A. Science Signaling, Vol. 12, Issue 610 https://doi.org/10.1126/scisignal.aax2057	journal	December 2019
Discovery of new GPCR ligands to illuminate new biology J. J., Irwin,; B. L., Roth,; B. K., Shoichet, Nature Publishing Group https://doi.org/10.17615/behz-bf42	text	January 2017

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
G protein-coupled receptors
X-ray crystallography