Cryptic pocket formation underlies allosteric modulator selectivity at muscarinic GPCRs

Scott A. Hollingsworth; Brendan Kelly; Celine Valant; Jordan Arthur Michaelis; Olivia Mastromihalis; Geoff Thompson; A. J. Venkatakrishnan; Samuel Hertig; Peter J. Scammells; Patrick M. Sexton; Christian C. Felder; Arthur Christopoulos; Ron O. Dror

doi:10.1038/s41467-019-11062-7

Nature Communications (Jul 2019)

Cryptic pocket formation underlies allosteric modulator selectivity at muscarinic GPCRs

Scott A. Hollingsworth,
Brendan Kelly,
Celine Valant,
Jordan Arthur Michaelis,
Olivia Mastromihalis,
Geoff Thompson,
A. J. Venkatakrishnan,
Samuel Hertig,
Peter J. Scammells,
Patrick M. Sexton,
Christian C. Felder,
Arthur Christopoulos,
Ron O. Dror

Affiliations

Scott A. Hollingsworth: Departments of Computer Science, Molecular and Cellular Physiology, and Structural Biology, and Institute for Computational and Mathematical Engineering, Stanford University
Brendan Kelly: Departments of Computer Science, Molecular and Cellular Physiology, and Structural Biology, and Institute for Computational and Mathematical Engineering, Stanford University
Celine Valant: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University
Jordan Arthur Michaelis: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University
Olivia Mastromihalis: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University
Geoff Thompson: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University
A. J. Venkatakrishnan: Departments of Computer Science, Molecular and Cellular Physiology, and Structural Biology, and Institute for Computational and Mathematical Engineering, Stanford University
Samuel Hertig: Departments of Computer Science, Molecular and Cellular Physiology, and Structural Biology, and Institute for Computational and Mathematical Engineering, Stanford University
Peter J. Scammells: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University
Patrick M. Sexton: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University
Christian C. Felder: Eli Lilly and Co., Neuroscience, Lilly Corporate Center
Arthur Christopoulos: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University
Ron O. Dror: Departments of Computer Science, Molecular and Cellular Physiology, and Structural Biology, and Institute for Computational and Mathematical Engineering, Stanford University

DOI: https://doi.org/10.1038/s41467-019-11062-7
Journal volume & issue: Vol. 10, no. 1
pp. 1 – 9

Abstract

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Allosteric GPCR modulators can achieve exquisite subtype selectivity, but the underlying mechanism is unclear. Using molecular dynamics simulations, the authors here identify a previously undetected dynamic pocket in muscarinic GPCRs that is critical for subtype selectivity of allosteric modulators.

Published in Nature Communications

ISSN: 2041-1723 (Online)
Publisher: Nature Portfolio
Country of publisher: United Kingdom
LCC subjects: Science
Website: https://www.nature.com/ncomms/

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