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

Title: 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.

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

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); 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 Organization:: ConfometRx, Santa Clara, CA (United States); Eli Lilly, Indianapolis, IN (United States); Eli Lilly, Windlesham (United Kingdom)

Grant/Contract Number:: W-31-109-ENG-38; Y1-CO-1020; Y1-GM-1104; APP1055134

OSTI ID:: 1248385

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

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 226 works

Citation information provided by
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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
Toward an understanding of the structural basis of allostery in muscarinic acetylcholine receptors Burger, Wessel A. C.; Sexton, Patrick M.; Christopoulos, Arthur Journal of General Physiology, Vol. 150, Issue 10 https://doi.org/10.1085/jgp.201711979	journal	September 2018
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
Ligand-guided homology modeling drives identification of novel histamine H3 receptor ligands Schaller, David; Hagenow, Stefanie; Stark, Holger PLOS ONE, Vol. 14, Issue 6 https://doi.org/10.1371/journal.pone.0218820	journal	June 2019
Key Targets for Multi-Target Ligands Designed to Combat Neurodegeneration Ramsay, Rona R.; Majekova, Magdalena; Medina, Milagros Frontiers in Neuroscience, Vol. 10 https://doi.org/10.3389/fnins.2016.00375	journal	August 2016
Crystal structure of dopamine receptor D4 bound to the subtype selective ligand, L745870 Zhou, Ye; Cao, Can; He, Lingli eLife, Vol. 8 https://doi.org/10.7554/elife.48822	journal	November 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
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
Designer receptor technology for the treatment of epilepsy Lieb, Andreas; Weston, Mikail; Kullmann, Dimitri M. EBioMedicine, Vol. 43 https://doi.org/10.1016/j.ebiom.2019.04.059	journal	May 2019
Chemogenetic Approach Using Ni(II) Complex–Agonist Conjugates Allows Selective Activation of Class A G-Protein-Coupled Receptors Kubota, Ryou; Nomura, Wataru; Iwasaka, Takuma ACS Central Science, Vol. 4, Issue 9 https://doi.org/10.1021/acscentsci.8b00390	journal	August 2018
Phencynonate S-isomer as a eutomer is a novel central anticholinergic drug for anti-motion sickness Xu, Pingxiang; Liu, Ying; Wang, Liyun Scientific Reports, Vol. 9, Issue 1 https://doi.org/10.1038/s41598-018-38305-9	journal	February 2019
Structure-guided development of selective M3 muscarinic acetylcholine receptor antagonists Liu, Hongtao; Hofmann, Josefa; Fish, Inbar Proceedings of the National Academy of Sciences, Vol. 115, Issue 47 https://doi.org/10.1073/pnas.1813988115	journal	November 2018
In Silico Studies Targeting G-protein Coupled Receptors for Drug Research Against Parkinson’s Disease Lemos, Agostinho; Melo, Rita; Preto, Antonio Jose Current Neuropharmacology, Vol. 16, Issue 6 https://doi.org/10.2174/1570159x16666180308161642	journal	June 2018
Current Advances in Allosteric Modulation of Muscarinic Receptors Jakubik, Jan; El-Fakahany, Esam E. Biomolecules, Vol. 10, Issue 2 https://doi.org/10.3390/biom10020325	journal	February 2020
G-Protein-Coupled Receptors in CNS: A Potential Therapeutic Target for Intervention in Neurodegenerative Disorders and Associated Cognitive Deficits Azam, Shofiul; Haque, Md. Ezazul; Jakaria, Md. Cells, Vol. 9, Issue 2 https://doi.org/10.3390/cells9020506	journal	February 2020
Recent Insights from Molecular Dynamics Simulations for G Protein-Coupled Receptor Drug Discovery International Journal of Molecular Sciences, Vol. 20, Issue 17 https://doi.org/10.3390/ijms20174237	journal	August 2019
Antinociceptive Effect of the Essential Oil from Croton conduplicatus Kunth (Euphorbiaceae) de Oliveira Júnior, Raimundo; Ferraz, Christiane; Silva, Juliane Molecules, Vol. 22, Issue 6 https://doi.org/10.3390/molecules22060900	journal	May 2017
Immunomodulatory Action of Substituted 1,3,4-Thiadiazines on the Course of Myocardial Infarction Sarapultsev, Alexey; Vassiliev, Pavel; Sarapultsev, Petr Molecules, Vol. 23, Issue 7 https://doi.org/10.3390/molecules23071611	journal	July 2018
Heterodimerization of Dibenzodiazepinone-Type Muscarinic Acetylcholine Receptor Ligands Leads to Increased M2R Affinity and Selectivity She, Xueke; Pegoli, Andrea; Mayr, Judith Universität Regensburg https://doi.org/10.5283/epub.36538	text	January 2017

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