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Mapping the Site of Action of Human P2X7 Receptor Antagonists AZ11645373, Brilliant Blue G, KN-62, Calmidazolium, and ZINC58368839 to the Intersubunit Allosteric Pocket
The P2X7 receptor is a trimeric ligand-gated ion channel activated by ATP. It is implicated in the cellular response to trauma/disease and considered to have significant therapeutic potential. Using chimeras and point mutants we have mapped the binding site of the P2X7R-selective antagonist AZ116453...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Pharmacology and Experimental Therapeutics
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6701605/ https://www.ncbi.nlm.nih.gov/pubmed/31263019 http://dx.doi.org/10.1124/mol.119.116715 |
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author | Bin Dayel, Anfal Evans, Richard J. Schmid, Ralf |
author_facet | Bin Dayel, Anfal Evans, Richard J. Schmid, Ralf |
author_sort | Bin Dayel, Anfal |
collection | PubMed |
description | The P2X7 receptor is a trimeric ligand-gated ion channel activated by ATP. It is implicated in the cellular response to trauma/disease and considered to have significant therapeutic potential. Using chimeras and point mutants we have mapped the binding site of the P2X7R-selective antagonist AZ11645373 to the known allosteric binding pocket at the interface between two subunits, in proximity to, but separated from the ATP binding site. Our structural model of AZ11645373 binding is consistent with effects of mutations on antagonist sensitivity, and the proposed binding mode explains variation in antagonist sensitivity between the human and rat P2X7 receptors. We have also determined the site of action for the P2X7R-selective antagonists ZINC58368839, brilliant blue G, KN-62, and calmidazolium. The effect of intersubunit allosteric pocket “signature mutants” F88A, T90V, D92A, F103A, and V312A on antagonist sensitivity suggests that ZINC58368839 comprises a binding mode similar to AZ11645373 and other previously characterized antagonists. For the larger antagonists, brilliant blue G, KN-62, and calmidazolium, our data imply an overlapping but distinct binding mode involving the central upper vestibule of the receptor in addition to the intersubunit allosteric pocket. Our work explains the site of action for a series of P2X7R antagonists and establishes “signature mutants” for P2X7R binding-mode characterization. |
format | Online Article Text |
id | pubmed-6701605 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | The American Society for Pharmacology and Experimental Therapeutics |
record_format | MEDLINE/PubMed |
spelling | pubmed-67016052019-09-04 Mapping the Site of Action of Human P2X7 Receptor Antagonists AZ11645373, Brilliant Blue G, KN-62, Calmidazolium, and ZINC58368839 to the Intersubunit Allosteric Pocket Bin Dayel, Anfal Evans, Richard J. Schmid, Ralf Mol Pharmacol Articles The P2X7 receptor is a trimeric ligand-gated ion channel activated by ATP. It is implicated in the cellular response to trauma/disease and considered to have significant therapeutic potential. Using chimeras and point mutants we have mapped the binding site of the P2X7R-selective antagonist AZ11645373 to the known allosteric binding pocket at the interface between two subunits, in proximity to, but separated from the ATP binding site. Our structural model of AZ11645373 binding is consistent with effects of mutations on antagonist sensitivity, and the proposed binding mode explains variation in antagonist sensitivity between the human and rat P2X7 receptors. We have also determined the site of action for the P2X7R-selective antagonists ZINC58368839, brilliant blue G, KN-62, and calmidazolium. The effect of intersubunit allosteric pocket “signature mutants” F88A, T90V, D92A, F103A, and V312A on antagonist sensitivity suggests that ZINC58368839 comprises a binding mode similar to AZ11645373 and other previously characterized antagonists. For the larger antagonists, brilliant blue G, KN-62, and calmidazolium, our data imply an overlapping but distinct binding mode involving the central upper vestibule of the receptor in addition to the intersubunit allosteric pocket. Our work explains the site of action for a series of P2X7R antagonists and establishes “signature mutants” for P2X7R binding-mode characterization. The American Society for Pharmacology and Experimental Therapeutics 2019-09 2019-09 /pmc/articles/PMC6701605/ /pubmed/31263019 http://dx.doi.org/10.1124/mol.119.116715 Text en Copyright © 2019 The Author(s). http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the CC BY Attribution 4.0 International license (http://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Articles Bin Dayel, Anfal Evans, Richard J. Schmid, Ralf Mapping the Site of Action of Human P2X7 Receptor Antagonists AZ11645373, Brilliant Blue G, KN-62, Calmidazolium, and ZINC58368839 to the Intersubunit Allosteric Pocket |
title | Mapping the Site of Action of Human P2X7 Receptor Antagonists AZ11645373, Brilliant Blue G, KN-62, Calmidazolium, and ZINC58368839 to the Intersubunit Allosteric Pocket |
title_full | Mapping the Site of Action of Human P2X7 Receptor Antagonists AZ11645373, Brilliant Blue G, KN-62, Calmidazolium, and ZINC58368839 to the Intersubunit Allosteric Pocket |
title_fullStr | Mapping the Site of Action of Human P2X7 Receptor Antagonists AZ11645373, Brilliant Blue G, KN-62, Calmidazolium, and ZINC58368839 to the Intersubunit Allosteric Pocket |
title_full_unstemmed | Mapping the Site of Action of Human P2X7 Receptor Antagonists AZ11645373, Brilliant Blue G, KN-62, Calmidazolium, and ZINC58368839 to the Intersubunit Allosteric Pocket |
title_short | Mapping the Site of Action of Human P2X7 Receptor Antagonists AZ11645373, Brilliant Blue G, KN-62, Calmidazolium, and ZINC58368839 to the Intersubunit Allosteric Pocket |
title_sort | mapping the site of action of human p2x7 receptor antagonists az11645373, brilliant blue g, kn-62, calmidazolium, and zinc58368839 to the intersubunit allosteric pocket |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6701605/ https://www.ncbi.nlm.nih.gov/pubmed/31263019 http://dx.doi.org/10.1124/mol.119.116715 |
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