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Structural and Dynamic Mechanisms of Allostery at the M4 Muscarinic Acetylcholine Receptor

79 Pages Posted: 14 Feb 2022 Publication Status: Review Complete

See all articles by Ziva Vuckovic

Ziva Vuckovic

Monash University - Drug Discovery Biology

Jinan Wang

University of Kansas - Center for Computational Biology and Department of Molecular Biosciences

Vi Pham

Monash University - Drug Discovery Biology

Jesse I. Mobbs

Monash University - Drug Discovery Biology

Matthew J. Belousoff

Monash University - Drug Discovery Biology

Apurba Bhattarai

University of Kansas - Center for Computational Biology and Department of Molecular Biosciences

Wessel A.C. Burger

Monash University - Drug Discovery Biology

Geoff Thompson

Monash University - Drug Discovery Biology

Mahmuda Yeasmin

Monash University - Drug Discovery Biology

Vindhya Nawaratne

Monash University - Drug Discovery Biology

Katie Leach

Monash University - Drug Discovery Biology

Emma T. van der Westhuizen

Monash University - Drug Discovery Biology

Elham Khajehali

Monash University - Drug Discovery Biology

Yi-Lynn Liang

Monash University - Drug Discovery Biology

Alisa Glukhova

Monash University - Drug Discovery Biology

Denise Wootten

Monash University - Drug Discovery Biology

Craig W. Lindsley

Vanderbilt University - Department of Pharmacology

Andrew Tobin

University of Glasgow - The Centre for Translational Pharmacology

Patrick M. Sexton

Monash University - Drug Discovery Biology

Radostin Danev

University of Tokyo - Graduate School of Medicine

Celine Valant

Monash University - Drug Discovery Biology

Yinglong Miao

University of Kansas - Center for Computational Biology and Department of Molecular Biosciences

Arthur Christopoulos

Monash University - Drug Discovery Biology

David Thal

Monash University - Drug Discovery Biology

More...

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 general principals governing the myriad pharmacological effects exerted by GPCR allosteric modulators remains limited. The M4 muscarinic acetylcholine receptor (M4 mAChR) is a well-validated and clinically relevant allosteric drug target. Here, we present high-resolution cryo-electron microscopy structures of the M4 mAChR bound to a cognate Gi1 protein and the high-affinity agonist, iperoxo, in the absence and presence of two different positive allosteric modulators, LY2033298 or VU0467154. We also determined the structure of the M4 mAChR-Gi1 complex bound to its endogenous agonist, ACh. Structural comparisons, together with molecular dynamics, mutagenesis and pharmacological characterization, provided unprecedented insights into the role of structure and dynamics in orthosteric and allosteric ligand binding, global mechanisms of receptor activation, cooperativity, probe-dependence, and species variability; key phenomena underpinning contemporary GPCR drug discovery.

Keywords: G protein coupled-receptor, M4 muscarinic acetylcholine receptor, allostery, cryoelectron microscopy, molecular dynamics, pharmacology, drug discovery

Suggested Citation

Vuckovic, Ziva and Wang, Jinan and Pham, Vi and Mobbs, Jesse I. and Belousoff, Matthew J. and Bhattarai, Apurba and Burger, Wessel A.C. and Thompson, Geoff and Yeasmin, Mahmuda and Nawaratne, Vindhya and Leach, Katie and van der Westhuizen, Emma T. and Khajehali, Elham and Liang, Yi-Lynn and Glukhova, Alisa and Wootten, Denise and Lindsley, Craig W. and Tobin, Andrew and Sexton, Patrick M. and Danev, Radostin and Valant, Celine and Miao, Yinglong and Christopoulos, Arthur and Thal, David, Structural and Dynamic Mechanisms of Allostery at the M4 Muscarinic Acetylcholine Receptor. Available at SSRN: https://ssrn.com/abstract=4034884 or http://dx.doi.org/10.2139/ssrn.4034884
This version of the paper has not been formally peer reviewed.

Ziva Vuckovic

Monash University - Drug Discovery Biology ( email )

Parkville, VIC 3052
Australia

Jinan Wang

University of Kansas - Center for Computational Biology and Department of Molecular Biosciences ( email )

KS 66045
United States

Vi Pham

Monash University - Drug Discovery Biology ( email )

Parkville, VIC 3052
Australia

Jesse I. Mobbs

Monash University - Drug Discovery Biology ( email )

Parkville, VIC 3052
Australia

Matthew J. Belousoff

Monash University - Drug Discovery Biology ( email )

Parkville, VIC 3052
Australia

Apurba Bhattarai

University of Kansas - Center for Computational Biology and Department of Molecular Biosciences ( email )

KS 66045
United States

Wessel A.C. Burger

Monash University - Drug Discovery Biology ( email )

Parkville, VIC 3052
Australia

Geoff Thompson

Monash University - Drug Discovery Biology ( email )

Parkville, VIC 3052
Australia

Mahmuda Yeasmin

Monash University - Drug Discovery Biology ( email )

Parkville, VIC 3052
Australia

Vindhya Nawaratne

Monash University - Drug Discovery Biology ( email )

Parkville, VIC 3052
Australia

Katie Leach

Monash University - Drug Discovery Biology ( email )

Parkville, VIC 3052
Australia

Emma T. Van der Westhuizen

Monash University - Drug Discovery Biology ( email )

Parkville, VIC 3052
Australia

Elham Khajehali

Monash University - Drug Discovery Biology ( email )

Parkville, VIC 3052
Australia

Yi-Lynn Liang

Monash University - Drug Discovery Biology ( email )

Parkville, VIC 3052
Australia

Alisa Glukhova

Monash University - Drug Discovery Biology ( email )

Parkville, VIC 3052
Australia

Denise Wootten

Monash University - Drug Discovery Biology ( email )

Parkville, VIC 3052
Australia

Craig W. Lindsley

Vanderbilt University - Department of Pharmacology ( email )

United States

Andrew Tobin

University of Glasgow - The Centre for Translational Pharmacology ( email )

Glasgow, G12 8QQ
United Kingdom

Patrick M. Sexton

Monash University - Drug Discovery Biology ( email )

Parkville, VIC 3052
Australia

Radostin Danev

University of Tokyo - Graduate School of Medicine ( email )

Hongo 7-3-1
Bunkyo-ku
Tokyo, 1130033
Japan

Celine Valant

Monash University - Drug Discovery Biology ( email )

Parkville, VIC 3052
Australia

Yinglong Miao

University of Kansas - Center for Computational Biology and Department of Molecular Biosciences ( email )

KS 66045
United States

Arthur Christopoulos

Monash University - Drug Discovery Biology ( email )

Parkville, VIC 3052
Australia

David Thal (Contact Author)

Monash University - Drug Discovery Biology ( email )

Parkville, VIC 3052
Australia

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