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Deciphering the agonist binding mechanism to the adenosine A1 receptor

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Deganutti, Giuseppe, Barkan, Kerry, Preti, Barbara, Leuenberger, Michele, Wall, Mark J., Frenguelli, Bruno G., Lochner, Martin, Ladds, Graham and Reynolds, Christopher A. (2021) Deciphering the agonist binding mechanism to the adenosine A1 receptor. ACS Pharmacology & Translational Science, 4 (1). pp. 314-326. doi:10.1021/acsptsci.0c00195

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Official URL: http://dx.doi.org/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.

Item Type: Journal Article
Subjects: Q Science > QP Physiology
Divisions: Faculty of Science > Life Sciences (2010- )
Library of Congress Subject Headings (LCSH): G proteins -- Receptors, Drug targeting, Adenosine -- Receptors
Journal or Publication Title: ACS Pharmacology & Translational Science
Publisher: American Chemical Society
ISSN: 2575-9108
Official Date: 12 February 2021
Dates:
DateEvent
12 February 2021Published
21 January 2021Available
18 January 2021Accepted
Date of first compliant deposit: 19 February 2021
Volume: 4
Number: 1
Page Range: pp. 314-326
DOI: 10.1021/acsptsci.0c00195
Status: Peer Reviewed
Publication Status: Published
Publisher Statement: This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Pharmacology & Translational Science, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/acsptsci.0c00195
Access rights to Published version: Restricted or Subscription Access
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
RPG-2017-255Leverhulme Trusthttp://dx.doi.org/10.13039/501100000275
UNSPECIFIED[RS] Royal Societyhttp://dx.doi.org/10.13039/501100000288
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