Pharmacological hallmarks of allostery at the M4 muscarinic receptor elucidated through structure and dynamics

Author:

Vuckovic Ziva1,Wang Jinan2,Pham Vi1,Mobbs Jesse I13,Belousoff Matthew J13,Bhattarai Apurba2,Burger Wessel AC13,Thompson Geoff1,Yeasmin Mahmuda1,Nawaratne Vindhya1,Leach Katie13,van der Westhuizen Emma T1ORCID,Khajehali Elham1,Liang Yi-Lynn1,Glukhova Alisa13,Wootten Denise13,Lindsley Craig W4,Tobin Andrew5ORCID,Sexton Patrick13,Danev Radostin6,Valant Celine1,Miao Yinglong2,Christopoulos Arthur137ORCID,Thal David M13ORCID

Affiliation:

1. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University

2. Center for Computational Biology and Department of Molecular Biosciences, University of Kansas

3. ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University

4. Department of Pharmacology, Warren Center for Neuroscience Drug Discovery and Department of Chemistry, Warren Center for Neuroscience Drug Discovery, Vanderbilt University

5. The Centre for Translational Pharmacology, Advanced Research Centre (ARC), College of Medical, Veterinary and Life Sciences, University of Glasgow

6. Graduate School of Medicine, University of Tokyo

7. Neuromedicines Discovery Centre, Monash University

Abstract

Allosteric modulation of G protein-coupled receptors (GPCRs) is a major paradigm in drug discovery. Despite decades of research, a molecular-level understanding of the general principles that govern the myriad pharmacological effects exerted by GPCR allosteric modulators remains limited. The M4 muscarinic acetylcholine receptor (M4 mAChR) is a validated and clinically relevant allosteric drug target for several major psychiatric and cognitive disorders. In this study, we rigorously quantified the affinity, efficacy, and magnitude of modulation of two different positive allosteric modulators, LY2033298 (LY298) and VU0467154 (VU154), combined with the endogenous agonist acetylcholine (ACh) or the high-affinity agonist iperoxo (Ipx), at the human M4 mAChR. By determining the cryo-electron microscopy structures of the M4 mAChR, bound to a cognate Gi1 protein and in complex with ACh, Ipx, LY298-Ipx, and VU154-Ipx, and applying molecular dynamics simulations, we determine key molecular mechanisms underlying allosteric pharmacology. In addition to delineating the contribution of spatially distinct binding sites on observed pharmacology, our findings also revealed a vital role for orthosteric and allosteric ligand–receptor–transducer complex stability, mediated by conformational dynamics between these sites, in the ultimate determination of affinity, efficacy, cooperativity, probe dependence, and species variability. There results provide a holistic framework for further GPCR mechanistic studies and can aid in the discovery and design of future allosteric drugs.

Funder

Wellcome Trust

National Health and Medical Research Council

Australian Research Council

National Institutes of Health

Takeda Science Foundation

Japan Science and Technology Agency

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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