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 () and Ron O. Dror ()
Additional contact information
Scott A. Hollingsworth: Stanford University
Brendan Kelly: Stanford University
Celine Valant: Monash University
Jordan Arthur Michaelis: Monash University
Olivia Mastromihalis: Monash University
Geoff Thompson: Monash University
A. J. Venkatakrishnan: Stanford University
Samuel Hertig: Stanford University
Peter J. Scammells: Monash University
Patrick M. Sexton: Monash University
Christian C. Felder: Eli Lilly and Co., Neuroscience, Lilly Corporate Center
Arthur Christopoulos: Monash University
Ron O. Dror: Stanford University

Nature Communications, 2019, vol. 10, issue 1, 1-9

Abstract: Abstract Allosteric modulators are highly desirable as drugs, particularly for G-protein-coupled receptor (GPCR) targets, because allosteric drugs can achieve selectivity between closely related receptors. The mechanisms by which allosteric modulators achieve selectivity remain elusive, however, particularly given recent structures that reveal similar allosteric binding sites across receptors. Here we show that positive allosteric modulators (PAMs) of the M1 muscarinic acetylcholine receptor (mAChR) achieve exquisite selectivity by occupying a dynamic pocket absent in existing crystal structures. This cryptic pocket forms far more frequently in molecular dynamics simulations of the M1 mAChR than in those of other mAChRs. These observations reconcile mutagenesis data that previously appeared contradictory. Further mutagenesis experiments validate our prediction that preventing cryptic pocket opening decreases the affinity of M1-selective PAMs. Our findings suggest opportunities for the design of subtype-specific drugs exploiting cryptic pockets that open in certain receptors but not in other receptors with nearly identical static structures.

Date: 2019
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DOI: 10.1038/s41467-019-11062-7

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