Video Experimental Relacionado
Updated: Jun 3, 2026
09:11
Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
Quelación de zinc con hidroxamato en las histonas desacetilasas moduladas por el acceso de agua al canal de unión del
Ruibo Wu1, Zhenyu Lu, Zexing Cao
1Department of Chemistry and State Key Laboratory of Physical Chemistry of Solid Surfaces, Xiamen University, Xiamen 361005, China.
Journal of the American Chemical Society
|April 5, 2011
Resumen
El desarrollo de inhibidores selectivos de la histona desacetilasa (HDAC) es crucial. Nuestro estudio revela que el enlace de enlace, no la protonación de ácido hidroxámico, dicta la especificidad de la inhibición de HDAC, guiando el diseño de fármacos futuros.
Área de la Ciencia:
- Bioquímica y Biología Molecular.
- Química Medicinal La Química Medicinal es un campo de estudio de la química medicinal.
- Biología computacional Biología computacional.
Sus antecedentes:
- El desarrollo de moduladores selectivos de histona desacetilasa (HDAC) es crítico para aplicaciones biológicas y médicas.
- Se conoce el papel del componente de enlace en la especificidad de la inhibición de HDAC, pero no se entiende completamente.
- Las hipótesis anteriores sugirieron que los diferentes estados de protonación del ácido hidroxámico explican los distintos modos de quelación del zinc-HDAC.
Objetivo del estudio:
- Para investigar el impacto del componente de enlace en la especificidad de la inhibición de HDAC.
- Para aclarar el mecanismo de quelación de hidroxamato-zinco en los HDAC.
- Proporcionar orientación para el diseño de nuevos inhibidores de HDAC específicos de la clase IIa.
Principales métodos:
- Empleado Born-Oppenheimer ab initio simulaciones QM / MM MD, una técnica avanzada para la simulación de metalloenzimas.
- Analizó el estado de unión y protonación del ácido hidroxámico tras la interacción con HDAC8.8.
- Investigó la influencia del acceso de agua al canal de unión del vinculante en los modos de quelación.
Principales resultados:
- Se confirmó que el ácido hidroxámico permanece protonado cuando se une a HDAC8, refutando hipótesis mecanicistas anteriores.
- Se identificó un nuevo mecanismo en el que el enlace del enlace y el acceso al agua modulan la quelación hidroxamato-zinco.
- Se demostró que el acceso de agua al canal de unión del enlace influye en el modo de quelación del hidroxamato con el ion zinc.
Conclusiones:
- El estado de protonación del ácido hidroxámico no es el determinante primario de los distintos modos de quelación del zinc-HDAC.
- Se propone un nuevo mecanismo que implique el acceso de agua al canal de unión del enlace que controla el modo de quelación.
- Este hallazgo ofrece información crucial para el diseño de inhibidores específicos de HDAC de clase IIa mediante la optimización de los componentes de enlace.
Más Videos Relacionados
Videos de Conceptos Relacionados
02:32Histone Modification
The histone proteins have a flexible N-terminal tail extending out from the nucleosome. These histone tails are often subjected to post-translational modifications such as acetylation, methylation, phosphorylation, and ubiquitination. Particular combinations of these modifications form “histone codes” that influence the chromatin folding and tissue-specific gene expression.
Acetylation
The enzyme histone acetyltransferase adds acetyl group to the histones. Another enzyme, histone deacetylase,...
Acetylation
The enzyme histone acetyltransferase adds acetyl group to the histones. Another enzyme, histone deacetylase,...
02:32Histone Modification
The histone proteins have a flexible N-terminal tail extending out from the nucleosome. These histone tails are often subjected to post-translational modifications such as acetylation, methylation, phosphorylation, and ubiquitination. Particular combinations of these modifications form “histone codes” that influence the chromatin folding and tissue-specific gene expression.
Acetylation
The enzyme histone acetyltransferase adds acetyl group to the histones. Another enzyme, histone deacetylase,...
Acetylation
The enzyme histone acetyltransferase adds acetyl group to the histones. Another enzyme, histone deacetylase,...
02:25Spreading of Chromatin Modifications
The histone proteins in the nucleosomes are post-translationally modified (PTM) to increase or decrease access to DNA. The commonly observed PTMs are methylation, acetylation, phosphorylation, and ubiquitination of lysine amino acids in the histone H3 tail region. These histone modifications have specific meaning for the cell. Hence, they are called "histone code". The protein complex involved in histone modification is termed as "reader-writer" complex.
Writers
The writer is an enzyme that can...
Writers
The writer is an enzyme that can...
02:54Nucleosome Remodeling
Nucleosomes are the basic units of chromatin compaction. Each nucleosome consists of the DNA bound tightly around a histone core, which makes the DNA inaccessible to DNA binding proteins such as DNA polymerase and RNA polymerase. Hence, the fundamental problem is to ensure access to DNA when appropriate, despite the compact and protective chromatin structure.
Nucleosome remodeling complex
Eukaryotic cells have specialized enzymes called ATP-dependent nucleosome remodeling enzymes. These enzymes...
Nucleosome remodeling complex
Eukaryotic cells have specialized enzymes called ATP-dependent nucleosome remodeling enzymes. These enzymes...
02:04Covalently Linked Protein Regulators
Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein.
These groups modify specific amino acids in a protein.
02:36Chromatin Immunoprecipitation- ChIP
Chromatin immunoprecipitation, or ChIP, is an antibody-based technique used to identify sites on DNA that bind to transcription factors of interest or histone proteins. It also helps determine the type of histone modifications such as acetylation, phosphorylation, or methylation.
Types of ChIP
ChIP can be divided into two types - X-ChIP and N-ChIP. X-ChIP involves in vivo cross-linking of histones and regulatory proteins to DNA, fragmenting the DNA by sonication, and isolating the protein-DNA...
Types of ChIP
ChIP can be divided into two types - X-ChIP and N-ChIP. X-ChIP involves in vivo cross-linking of histones and regulatory proteins to DNA, fragmenting the DNA by sonication, and isolating the protein-DNA...