Deciphering the Agonist Binding Mechanism to the Adenosine A1 Receptor

Giuseppe Deganutti; Kerry Barkan; Barbara Preti; Michele Leuenberger; Mark Wall; Bruno G Frenguelli; Martin Lochner; Graham Ladds; Christopher A Reynolds

doi:10.1021/acsptsci.0c00195

Deciphering the Agonist Binding Mechanism to the Adenosine A1 Receptor

Giuseppe Deganutti, Kerry Barkan, Barbara Preti, Michele Leuenberger, Mark Wall, Bruno G Frenguelli, Martin Lochner, Graham Ladds, Christopher A Reynolds

Research output: Contribution to journal › Article › peer-review

7 Citations (Scopus)

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Abstract

Despite being among the most characterized G protein-coupled receptors (GPCRs), adenosine receptors (ARs) have always been a difficult target in drug design. To date, no agonist other than the natural effector and the diagnostic regadenoson has been approved for human use. Recently, the structure of the adenosine A1 receptor (A1R) was determined in the active, Gi protein complexed state; this has important repercussions for structure-based drug design. Here, we employed supervised molecular dynamics simulations and mutagenesis experiments to extend the structural knowledge of the binding of selective agonists to A1R. Our results identify new residues involved in the association and dissociation pathway, they suggest the binding mode of N6-cyclopentyladenosine (CPA) related ligands, and they highlight the dramatic effect that chemical modifications can have on the overall binding mechanism, paving the way for the rational development of a structure-kinetics relationship of A1R agonists.

Original language	English
Pages (from-to)	314-326
Number of pages	13
Journal	ACS Pharmacology and Translational Science
Volume	4
Issue number	1
Early online date	20 Jan 2021
DOIs	https://doi.org/10.1021/acsptsci.0c00195
Publication status	Published - 12 Feb 2021

Bibliographical note

This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Pharmacology and Translational Science, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://dx.doi.org/10.1021/acsptsci.0c00195

Funder

Leverhulme Trust (Grant RPG-2017-255, C.A.R. and G.L. to fund K.B. and G.D.)

Keywords

G protein coupled receptors
GPCRs
Adenosine A1 receptor
A1R supervised molecular dynamics
SuMD
mutagenesis experiments
binding
Binding
A R
Mutagenesis experiments
Supervised molecular dynamics

ASJC Scopus subject areas

Pharmacology (medical)
Pharmacology

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10.1021/acsptsci.0c00195

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abstract = "Despite being among the most characterized G protein-coupled receptors (GPCRs), adenosine receptors (ARs) have always been a difficult target in drug design. To date, no agonist other than the natural effector and the diagnostic regadenoson has been approved for human use. Recently, the structure of the adenosine A1 receptor (A1R) was determined in the active, Gi protein complexed state; this has important repercussions for structure-based drug design. Here, we employed supervised molecular dynamics simulations and mutagenesis experiments to extend the structural knowledge of the binding of selective agonists to A1R. Our results identify new residues involved in the association and dissociation pathway, they suggest the binding mode of N6-cyclopentyladenosine (CPA) related ligands, and they highlight the dramatic effect that chemical modifications can have on the overall binding mechanism, paving the way for the rational development of a structure-kinetics relationship of A1R agonists.",

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AU - Wall, Mark

AU - Frenguelli, Bruno G

AU - Lochner, Martin

AU - Ladds, Graham

AU - Reynolds, Christopher A

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N2 - Despite being among the most characterized G protein-coupled receptors (GPCRs), adenosine receptors (ARs) have always been a difficult target in drug design. To date, no agonist other than the natural effector and the diagnostic regadenoson has been approved for human use. Recently, the structure of the adenosine A1 receptor (A1R) was determined in the active, Gi protein complexed state; this has important repercussions for structure-based drug design. Here, we employed supervised molecular dynamics simulations and mutagenesis experiments to extend the structural knowledge of the binding of selective agonists to A1R. Our results identify new residues involved in the association and dissociation pathway, they suggest the binding mode of N6-cyclopentyladenosine (CPA) related ligands, and they highlight the dramatic effect that chemical modifications can have on the overall binding mechanism, paving the way for the rational development of a structure-kinetics relationship of A1R agonists.

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Deciphering the Agonist Binding Mechanism to the Adenosine A1 Receptor

Abstract

Bibliographical note

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Keywords

ASJC Scopus subject areas

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