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Make the right measurement: Discovery of an allosteric inhibition site for p300-HAT
Histone acetyltransferases (HATs) and histone deacetylases (HDACs) catalyze the dynamic and reversible acetylation of proteins, an epigenetic regulatory mechanism associated with multiple cancers. Indeed, HDAC inhibitors are already approved in the clinic. The HAT paralogs p300 and CREB-binding prot...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Crystallographic Association
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800282/ https://www.ncbi.nlm.nih.gov/pubmed/31649965 http://dx.doi.org/10.1063/1.5119336 |
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author | Gardberg, Anna S. Huhn, Annissa J. Cummings, Richard Bommi-Reddy, Archana Poy, Florence Setser, Jeremy Vivat, Valerie Brucelle, Francois Wilson, Jonathan |
author_facet | Gardberg, Anna S. Huhn, Annissa J. Cummings, Richard Bommi-Reddy, Archana Poy, Florence Setser, Jeremy Vivat, Valerie Brucelle, Francois Wilson, Jonathan |
author_sort | Gardberg, Anna S. |
collection | PubMed |
description | Histone acetyltransferases (HATs) and histone deacetylases (HDACs) catalyze the dynamic and reversible acetylation of proteins, an epigenetic regulatory mechanism associated with multiple cancers. Indeed, HDAC inhibitors are already approved in the clinic. The HAT paralogs p300 and CREB-binding protein (CBP) have been implicated in human pathological conditions including several hematological malignancies and androgen receptor-positive prostate cancer. Others have reported CoA-competitive inhibitors of p300 and CBP with cell-based activity. Here, we describe 2 compounds, CPI-076 and CPI-090, discovered through p300-HAT high throughput screening screening, which inhibit p300-HAT via binding at an allosteric site. We present the high resolution (1.7 and 2.3 Å) co-crystal structures of these molecules bound to a previously undescribed allosteric site of p300-HAT. Derivatization yielded actionable structure-activity relationships, but the full-length enzymatic assay demonstrated that this allosteric HAT inhibitor series was artifactual, inhibiting only the HAT domain of p300 with no effect on the full-length enzyme. |
format | Online Article Text |
id | pubmed-6800282 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | American Crystallographic Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-68002822019-10-24 Make the right measurement: Discovery of an allosteric inhibition site for p300-HAT Gardberg, Anna S. Huhn, Annissa J. Cummings, Richard Bommi-Reddy, Archana Poy, Florence Setser, Jeremy Vivat, Valerie Brucelle, Francois Wilson, Jonathan Struct Dyn ARTICLES Histone acetyltransferases (HATs) and histone deacetylases (HDACs) catalyze the dynamic and reversible acetylation of proteins, an epigenetic regulatory mechanism associated with multiple cancers. Indeed, HDAC inhibitors are already approved in the clinic. The HAT paralogs p300 and CREB-binding protein (CBP) have been implicated in human pathological conditions including several hematological malignancies and androgen receptor-positive prostate cancer. Others have reported CoA-competitive inhibitors of p300 and CBP with cell-based activity. Here, we describe 2 compounds, CPI-076 and CPI-090, discovered through p300-HAT high throughput screening screening, which inhibit p300-HAT via binding at an allosteric site. We present the high resolution (1.7 and 2.3 Å) co-crystal structures of these molecules bound to a previously undescribed allosteric site of p300-HAT. Derivatization yielded actionable structure-activity relationships, but the full-length enzymatic assay demonstrated that this allosteric HAT inhibitor series was artifactual, inhibiting only the HAT domain of p300 with no effect on the full-length enzyme. American Crystallographic Association 2019-10-11 /pmc/articles/PMC6800282/ /pubmed/31649965 http://dx.doi.org/10.1063/1.5119336 Text en © 2019 Author(s). 2329-7778/2019/6(5)/054702/5 All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | ARTICLES Gardberg, Anna S. Huhn, Annissa J. Cummings, Richard Bommi-Reddy, Archana Poy, Florence Setser, Jeremy Vivat, Valerie Brucelle, Francois Wilson, Jonathan Make the right measurement: Discovery of an allosteric inhibition site for p300-HAT |
title | Make the right measurement: Discovery of an allosteric inhibition site for p300-HAT |
title_full | Make the right measurement: Discovery of an allosteric inhibition site for p300-HAT |
title_fullStr | Make the right measurement: Discovery of an allosteric inhibition site for p300-HAT |
title_full_unstemmed | Make the right measurement: Discovery of an allosteric inhibition site for p300-HAT |
title_short | Make the right measurement: Discovery of an allosteric inhibition site for p300-HAT |
title_sort | make the right measurement: discovery of an allosteric inhibition site for p300-hat |
topic | ARTICLES |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800282/ https://www.ncbi.nlm.nih.gov/pubmed/31649965 http://dx.doi.org/10.1063/1.5119336 |
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