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J Gen Physiol. 2019 Jul 1;151(7):898-911. doi: 10.1085/jgp.201912347. Epub 2019 May 24.

Molecular determinants for agonist recognition and discrimination in P2X2 receptors.

Author information

1
Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
2
Biomolecular Nanoscale Engineering Center, Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense, Denmark.
3
University of Strasbourg, Centre National de la Recherche Scientifique, Conception et Application de Molécules Bioactives Unité Mixte de Recherche 7199, Strasbourg, France.
4
Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark stephan.pless@sund.ku.dk.

Abstract

P2X receptors (P2XRs) are trimeric ligand-gated ion channels that open a cation-selective pore in response to ATP binding. P2XRs contribute to synaptic transmission and are involved in pain and inflammation, thus representing valuable drug targets. Recent crystal structures have confirmed the findings of previous studies with regards to the amino acid chains involved in ligand recognition, but they have also suggested that backbone carbonyl atoms contribute to ATP recognition and discrimination. Here we use a combination of site-directed mutagenesis, amide-to-ester substitutions, and a range of ATP analogues with subtle alterations to either base or sugar component to investigate the contributions of backbone carbonyl atoms toward ligand recognition and discrimination in rat P2X2Rs. Our findings demonstrate that while the Lys69 backbone carbonyl makes an important contribution to ligand recognition, the discrimination between different ligands is mediated by both the side chain and the backbone carbonyl oxygen of Thr184. Together, our data demonstrate how conserved elements in P2X2Rs recognize and discriminate agonists.

PMID:
31126967
PMCID:
PMC6605687
[Available on 2020-01-01]
DOI:
10.1085/jgp.201912347

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