Video Experimental Relacionado
Updated: May 28, 2025
09:15
Monitoring Protein-RNA Interaction Dynamics In Vivo at High Temporal Resolution Using χCRAC
Published on: May 9, 2020
4.9K
UM171 pega el conjunto asimétrico CRL3-HDAC1/2 para degradar los compresores de núcleo CoREST
Megan J R Yeo1,2, Olivia Zhang1,2, Xiaowen Xie3,4
1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
Nature
|February 12, 2025
Resumen
UM171 actúa como un pegamento molecular, vinculando KBTBD4 a HDAC1/ 2 para promover la degradación del corepresor y mejorar la auto-renovación de las células madre hematopoyéticas. Esto revela un nuevo mecanismo para los degradantes de moléculas pequeñas dirigidos a los complejos de ligasa E3.
Área de la Ciencia:
- La bioquímica
- Biología molecular
- Descubrimiento de drogas
Sus antecedentes:
- UM171 mejora la auto-renovación de las células madre hematopoyéticas humanas ex vivo.
- El mecanismo de UM171 involucra el complejo CUL3-RING E3 ubiquitin ligase (CRL3) y KBTBD4.
- El objetivo directo y el mecanismo preciso de UM171 no estaban claros anteriormente.
Objetivo del estudio:
- Aclarar el objetivo directo y el mecanismo de acción de UM171.
- Comprender cómo UM171 induce interacciones entre KBTBD4 y sus objetivos.
- Investigar las bases estructurales de la degradación mediada por UM171.
Principales métodos:
- Estudios proteómicos y de inhibidores químicos para identificar el objetivo de UM171.
- Microscopía cryoelectrónica para determinar la estructura del complejo.
- Escaneo del editor de base para validar las interacciones funcionales.
Principales resultados:
- UM171 funciona como un pegamento molecular, induciendo interacciones de alta afinidad entre KBTBD4 y HDAC1/ 2.
- HDAC1/2 se identifican como los objetivos principales de UM171.
- Cryo-EM reveló un ensamblaje asimétrico donde UM171 conecta KBTBD4 y HDAC1, con inositol hexakisfosfato estabilizando aún más el complejo.
Conclusiones:
- El mecanismo de UM171 implica la orientación directa de HDAC1 / 2 a través de un mecanismo de pegamento molecular.
- El estudio pone de manifiesto la base estructural de la acción de UM171, poniendo de relieve la vinculación cooperativa.
- Este trabajo proporciona información sobre el aprovechamiento de la cooperatividad de la ligasa E3 dimérica para la degradación de proteínas dirigida.
Más Videos Relacionados
Videos de Conceptos Relacionados
02:04Co-activators and Co-repressors
7.2K
Gene transcription is regulated by the synergistic action of several proteins that form a complex at a gene regulatory site. This is observed in eukaryotes, where the regulation of gene expression is a complex process. Regulatory proteins in eukaryotes can broadly be classified into two types – regulators that bind directly to specific DNA sequences and co-regulators that associate with regulatory proteins but cannot directly bind to the DNA. These co-regulators are further divided into...
7.2K
02:58Regulated Protein Degradation
2.5K
2.5K
02:54Nucleosome Remodeling
8.9K
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...
8.9K
01:45Regulation of Nuclear Protein Sorting
2.4K
Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the...
2.4K
02:25Spreading of Chromatin Modifications
8.2K
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...
Writers
The writer...
8.2K
02:04Covalently Linked Protein Regulators
6.8K
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....
6.8K