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Differential Epitope Mapping by STD NMR Spectroscopy To Reveal the Nature of Protein–Ligand Contacts

Saturation transfer difference (STD) NMR spectroscopy is extensively used to obtain epitope maps of ligands binding to protein receptors, thereby revealing structural details of the interaction, which is key to direct lead optimization efforts in drug discovery. However, it does not give information...

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Detalles Bibliográficos
Autores principales: Monaco, Serena, Tailford, Louise E., Juge, Nathalie, Angulo, Jesus
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5725711/
https://www.ncbi.nlm.nih.gov/pubmed/28977722
http://dx.doi.org/10.1002/anie.201707682
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author Monaco, Serena
Tailford, Louise E.
Juge, Nathalie
Angulo, Jesus
author_facet Monaco, Serena
Tailford, Louise E.
Juge, Nathalie
Angulo, Jesus
author_sort Monaco, Serena
collection PubMed
description Saturation transfer difference (STD) NMR spectroscopy is extensively used to obtain epitope maps of ligands binding to protein receptors, thereby revealing structural details of the interaction, which is key to direct lead optimization efforts in drug discovery. However, it does not give information about the nature of the amino acids surrounding the ligand in the binding pocket. Herein, we report the development of the novel method differential epitope mapping by STD NMR (DEEP‐STD NMR) for identifying the type of protein residues contacting the ligand. The method produces differential epitope maps through 1) differential frequency STD NMR and/or 2) differential solvent (D(2)O/H(2)O) STD NMR experiments. The two approaches provide different complementary information on the binding pocket. We demonstrate that DEEP‐STD NMR can be used to readily obtain pharmacophore information on the protein. Furthermore, if the 3D structure of the protein is known, this information also helps in orienting the ligand in the binding pocket.
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spelling pubmed-57257112017-12-12 Differential Epitope Mapping by STD NMR Spectroscopy To Reveal the Nature of Protein–Ligand Contacts Monaco, Serena Tailford, Louise E. Juge, Nathalie Angulo, Jesus Angew Chem Int Ed Engl Communications Saturation transfer difference (STD) NMR spectroscopy is extensively used to obtain epitope maps of ligands binding to protein receptors, thereby revealing structural details of the interaction, which is key to direct lead optimization efforts in drug discovery. However, it does not give information about the nature of the amino acids surrounding the ligand in the binding pocket. Herein, we report the development of the novel method differential epitope mapping by STD NMR (DEEP‐STD NMR) for identifying the type of protein residues contacting the ligand. The method produces differential epitope maps through 1) differential frequency STD NMR and/or 2) differential solvent (D(2)O/H(2)O) STD NMR experiments. The two approaches provide different complementary information on the binding pocket. We demonstrate that DEEP‐STD NMR can be used to readily obtain pharmacophore information on the protein. Furthermore, if the 3D structure of the protein is known, this information also helps in orienting the ligand in the binding pocket. John Wiley and Sons Inc. 2017-10-23 2017-11-27 /pmc/articles/PMC5725711/ /pubmed/28977722 http://dx.doi.org/10.1002/anie.201707682 Text en © 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Communications
Monaco, Serena
Tailford, Louise E.
Juge, Nathalie
Angulo, Jesus
Differential Epitope Mapping by STD NMR Spectroscopy To Reveal the Nature of Protein–Ligand Contacts
title Differential Epitope Mapping by STD NMR Spectroscopy To Reveal the Nature of Protein–Ligand Contacts
title_full Differential Epitope Mapping by STD NMR Spectroscopy To Reveal the Nature of Protein–Ligand Contacts
title_fullStr Differential Epitope Mapping by STD NMR Spectroscopy To Reveal the Nature of Protein–Ligand Contacts
title_full_unstemmed Differential Epitope Mapping by STD NMR Spectroscopy To Reveal the Nature of Protein–Ligand Contacts
title_short Differential Epitope Mapping by STD NMR Spectroscopy To Reveal the Nature of Protein–Ligand Contacts
title_sort differential epitope mapping by std nmr spectroscopy to reveal the nature of protein–ligand contacts
topic Communications
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5725711/
https://www.ncbi.nlm.nih.gov/pubmed/28977722
http://dx.doi.org/10.1002/anie.201707682
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