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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 ISSN 2575-9108.
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WRAP-deciphering-agonist-binding-mechanism-adenosine-A1-receptor-2021.pdf - Accepted Version - Requires a PDF viewer. Download (2122Kb) | Preview |
Official URL: http://dx.doi.org/10.1021/acsptsci.0c00195
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 | |||||||||
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| Subjects: | Q Science > QP Physiology | |||||||||
| Divisions: | Faculty of Science, Engineering and Medicine > 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: |
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| Volume: | 4 | |||||||||
| Number: | 1 | |||||||||
| Page Range: | pp. 314-326 | |||||||||
| DOI: | 10.1021/acsptsci.0c00195 | |||||||||
| Status: | Peer Reviewed | |||||||||
| Publication Status: | Published | |||||||||
| Reuse Statement (publisher, data, author rights): | 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 | |||||||||
| Date of first compliant deposit: | 19 February 2021 | |||||||||
| Date of first compliant Open Access: | 21 January 2022 | |||||||||
| RIOXX Funder/Project Grant: |
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