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Identifying requirements for RSK2 specific inhibitors
Identifying isoform-specific inhibitors for closely related kinase family members remains a substantial challenge. The necessity for achieving this specificity is exemplified by the RSK family, downstream effectors of ERK1/2, which have divergent physiological effects. The natural product, SL0101, a...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8344253/ https://www.ncbi.nlm.nih.gov/pubmed/34348556 http://dx.doi.org/10.1080/14756366.2021.1957862 |
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author | Wright, Eric B. Fukuda, Shinji Li, Mingzong Li, Yu O’Doherty, George A. Lannigan, Deborah A. |
author_facet | Wright, Eric B. Fukuda, Shinji Li, Mingzong Li, Yu O’Doherty, George A. Lannigan, Deborah A. |
author_sort | Wright, Eric B. |
collection | PubMed |
description | Identifying isoform-specific inhibitors for closely related kinase family members remains a substantial challenge. The necessity for achieving this specificity is exemplified by the RSK family, downstream effectors of ERK1/2, which have divergent physiological effects. The natural product, SL0101, a flavonoid glycoside, binds specifically to RSK1/2 through a binding pocket generated by an extensive conformational rearrangement within the RSK N-terminal kinase domain (NTKD). In modelling experiments a single amino acid that is divergent in RSK3/4 most likely prevents the required conformational rearrangement necessary for SL0101 binding. Kinetic analysis of RSK2 association with SL0101 and its derivatives identified that regions outside of the NTKD contribute to stable inhibitor binding. An analogue with an n-propyl-carbamate at the 4” position on the rhamnose moiety was identified that forms a highly stable inhibitor complex with RSK2 but not with RSK1. These results identify a SL0101 modification that will aid the identification of RSK2 specific inhibitors. |
format | Online Article Text |
id | pubmed-8344253 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-83442532021-08-09 Identifying requirements for RSK2 specific inhibitors Wright, Eric B. Fukuda, Shinji Li, Mingzong Li, Yu O’Doherty, George A. Lannigan, Deborah A. J Enzyme Inhib Med Chem Research Paper Identifying isoform-specific inhibitors for closely related kinase family members remains a substantial challenge. The necessity for achieving this specificity is exemplified by the RSK family, downstream effectors of ERK1/2, which have divergent physiological effects. The natural product, SL0101, a flavonoid glycoside, binds specifically to RSK1/2 through a binding pocket generated by an extensive conformational rearrangement within the RSK N-terminal kinase domain (NTKD). In modelling experiments a single amino acid that is divergent in RSK3/4 most likely prevents the required conformational rearrangement necessary for SL0101 binding. Kinetic analysis of RSK2 association with SL0101 and its derivatives identified that regions outside of the NTKD contribute to stable inhibitor binding. An analogue with an n-propyl-carbamate at the 4” position on the rhamnose moiety was identified that forms a highly stable inhibitor complex with RSK2 but not with RSK1. These results identify a SL0101 modification that will aid the identification of RSK2 specific inhibitors. Taylor & Francis 2021-08-05 /pmc/articles/PMC8344253/ /pubmed/34348556 http://dx.doi.org/10.1080/14756366.2021.1957862 Text en © 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Paper Wright, Eric B. Fukuda, Shinji Li, Mingzong Li, Yu O’Doherty, George A. Lannigan, Deborah A. Identifying requirements for RSK2 specific inhibitors |
title | Identifying requirements for RSK2 specific inhibitors |
title_full | Identifying requirements for RSK2 specific inhibitors |
title_fullStr | Identifying requirements for RSK2 specific inhibitors |
title_full_unstemmed | Identifying requirements for RSK2 specific inhibitors |
title_short | Identifying requirements for RSK2 specific inhibitors |
title_sort | identifying requirements for rsk2 specific inhibitors |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8344253/ https://www.ncbi.nlm.nih.gov/pubmed/34348556 http://dx.doi.org/10.1080/14756366.2021.1957862 |
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