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Highly selective inhibition of histone demethylases by de novo macrocyclic peptides
The JmjC histone demethylases (KDMs) are linked to tumour cell proliferation and are current cancer targets; however, very few highly selective inhibitors for these are available. Here we report cyclic peptide inhibitors of the KDM4A-C with selectivity over other KDMs/2OG oxygenases, including close...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5384220/ https://www.ncbi.nlm.nih.gov/pubmed/28382930 http://dx.doi.org/10.1038/ncomms14773 |
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author | Kawamura, Akane Münzel, Martin Kojima, Tatsuya Yapp, Clarence Bhushan, Bhaskar Goto, Yuki Tumber, Anthony Katoh, Takayuki King, Oliver N. F. Passioura, Toby Walport, Louise J. Hatch, Stephanie B. Madden, Sarah Müller, Susanne Brennan, Paul E. Chowdhury, Rasheduzzaman Hopkinson, Richard J. Suga, Hiroaki Schofield, Christopher J. |
author_facet | Kawamura, Akane Münzel, Martin Kojima, Tatsuya Yapp, Clarence Bhushan, Bhaskar Goto, Yuki Tumber, Anthony Katoh, Takayuki King, Oliver N. F. Passioura, Toby Walport, Louise J. Hatch, Stephanie B. Madden, Sarah Müller, Susanne Brennan, Paul E. Chowdhury, Rasheduzzaman Hopkinson, Richard J. Suga, Hiroaki Schofield, Christopher J. |
author_sort | Kawamura, Akane |
collection | PubMed |
description | The JmjC histone demethylases (KDMs) are linked to tumour cell proliferation and are current cancer targets; however, very few highly selective inhibitors for these are available. Here we report cyclic peptide inhibitors of the KDM4A-C with selectivity over other KDMs/2OG oxygenases, including closely related KDM4D/E isoforms. Crystal structures and biochemical analyses of one of the inhibitors (CP2) with KDM4A reveals that CP2 binds differently to, but competes with, histone substrates in the active site. Substitution of the active site binding arginine of CP2 to N-ɛ-trimethyl-lysine or methylated arginine results in cyclic peptide substrates, indicating that KDM4s may act on non-histone substrates. Targeted modifications to CP2 based on crystallographic and mass spectrometry analyses results in variants with greater proteolytic robustness. Peptide dosing in cells manifests KDM4A target stabilization. Although further development is required to optimize cellular activity, the results reveal the feasibility of highly selective non-metal chelating, substrate-competitive inhibitors of the JmjC KDMs. |
format | Online Article Text |
id | pubmed-5384220 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-53842202017-04-23 Highly selective inhibition of histone demethylases by de novo macrocyclic peptides Kawamura, Akane Münzel, Martin Kojima, Tatsuya Yapp, Clarence Bhushan, Bhaskar Goto, Yuki Tumber, Anthony Katoh, Takayuki King, Oliver N. F. Passioura, Toby Walport, Louise J. Hatch, Stephanie B. Madden, Sarah Müller, Susanne Brennan, Paul E. Chowdhury, Rasheduzzaman Hopkinson, Richard J. Suga, Hiroaki Schofield, Christopher J. Nat Commun Article The JmjC histone demethylases (KDMs) are linked to tumour cell proliferation and are current cancer targets; however, very few highly selective inhibitors for these are available. Here we report cyclic peptide inhibitors of the KDM4A-C with selectivity over other KDMs/2OG oxygenases, including closely related KDM4D/E isoforms. Crystal structures and biochemical analyses of one of the inhibitors (CP2) with KDM4A reveals that CP2 binds differently to, but competes with, histone substrates in the active site. Substitution of the active site binding arginine of CP2 to N-ɛ-trimethyl-lysine or methylated arginine results in cyclic peptide substrates, indicating that KDM4s may act on non-histone substrates. Targeted modifications to CP2 based on crystallographic and mass spectrometry analyses results in variants with greater proteolytic robustness. Peptide dosing in cells manifests KDM4A target stabilization. Although further development is required to optimize cellular activity, the results reveal the feasibility of highly selective non-metal chelating, substrate-competitive inhibitors of the JmjC KDMs. Nature Publishing Group 2017-04-06 /pmc/articles/PMC5384220/ /pubmed/28382930 http://dx.doi.org/10.1038/ncomms14773 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Kawamura, Akane Münzel, Martin Kojima, Tatsuya Yapp, Clarence Bhushan, Bhaskar Goto, Yuki Tumber, Anthony Katoh, Takayuki King, Oliver N. F. Passioura, Toby Walport, Louise J. Hatch, Stephanie B. Madden, Sarah Müller, Susanne Brennan, Paul E. Chowdhury, Rasheduzzaman Hopkinson, Richard J. Suga, Hiroaki Schofield, Christopher J. Highly selective inhibition of histone demethylases by de novo macrocyclic peptides |
title | Highly selective inhibition of histone demethylases by de novo macrocyclic peptides |
title_full | Highly selective inhibition of histone demethylases by de novo macrocyclic peptides |
title_fullStr | Highly selective inhibition of histone demethylases by de novo macrocyclic peptides |
title_full_unstemmed | Highly selective inhibition of histone demethylases by de novo macrocyclic peptides |
title_short | Highly selective inhibition of histone demethylases by de novo macrocyclic peptides |
title_sort | highly selective inhibition of histone demethylases by de novo macrocyclic peptides |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5384220/ https://www.ncbi.nlm.nih.gov/pubmed/28382930 http://dx.doi.org/10.1038/ncomms14773 |
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