Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Gardberg, Anna S., Huhn, Annissa J., Cummings, Richard, Bommi-Reddy, Archana, Poy, Florence, Setser, Jeremy, Vivat, Valerie, Brucelle, Francois, Wilson, Jonathan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Crystallographic Association 2019
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
_version_ 1783460418351529984
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
work_keys_str_mv AT gardbergannas maketherightmeasurementdiscoveryofanallostericinhibitionsiteforp300hat
AT huhnannissaj maketherightmeasurementdiscoveryofanallostericinhibitionsiteforp300hat
AT cummingsrichard maketherightmeasurementdiscoveryofanallostericinhibitionsiteforp300hat
AT bommireddyarchana maketherightmeasurementdiscoveryofanallostericinhibitionsiteforp300hat
AT poyflorence maketherightmeasurementdiscoveryofanallostericinhibitionsiteforp300hat
AT setserjeremy maketherightmeasurementdiscoveryofanallostericinhibitionsiteforp300hat
AT vivatvalerie maketherightmeasurementdiscoveryofanallostericinhibitionsiteforp300hat
AT brucellefrancois maketherightmeasurementdiscoveryofanallostericinhibitionsiteforp300hat
AT wilsonjonathan maketherightmeasurementdiscoveryofanallostericinhibitionsiteforp300hat