Video Experimental Relacionado
Updated: May 7, 2026
12:40
A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
Bases estructurales para la autoinhibición de la c-Abl tirosina quinasa
Bhushan Nagar1, Oliver Hantschel, Matthew A Young
1Howard Hughes Medical Institute and Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Cell
|March 26, 2003
Resumen
La leucemia mielógena crónica (LMC) implica la desregulación de la c-Abl. La misristoilación de c-Abl 1b induce la autoinhibición, similar a las Src quinasas, lo que explica el uso de Gleevec.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Molecular Biología Molecular
- Oncología Oncología.
Sus antecedentes:
- La desregulación de c-Abl está implicada en la leucemia mielógena crónica (LMC).
- El mecanismo autoinhibidor de c-Abl no ha quedado claro debido a su falta de un residuo específico de fosfotirosina que se encuentra en las Src kinasas.
- Comprender la regulación c-Abl es crucial para las estrategias de tratamiento de la LMC.
Objetivo del estudio:
- Para dilucidar el mecanismo autoinhibidor de c-Abl.
- Investigar la base estructural para la regulación de c-Abl y su respuesta diferencial a imatinib.
- Proporcionar información sobre los distintos comportamientos de las quinasas c-Abl y c-Src.
Principales métodos:
- Análisis de las estructuras cristalinas de c-Abl.
- Investigación del papel de la miristoilación N-terminal en la conformación c-Abl.
- Análisis estructural comparativo con las Src. kinases.
Principales resultados:
- La modificación N-terminal de myristoyl de c-Abl 1b se une al dominio de la quinasa, induciendo cambios conformacionales.
- Estos cambios facilitan el acoplamiento de los dominios SH2 y SH3, formando un estado autoinhibido.
- La estructura autoinhibida de c-Abl comparte similitudes con las inactivas cinasas Src pero tiene diferencias clave.
Conclusiones:
- La misristoilación es crítica para la autoinhibición de c-Abl.
- Las diferencias estructurales explican por qué el imatinib (Gleevec) inhibe el Abl pero no el Src.
- Esto proporciona una base molecular para la terapia dirigida de la LMC.
Videos de Conceptos Relacionados
02:34Inhibition of Cdk Activity
The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
01:19Allosteric Proteins-ATCase
Binding sites linkages can regulate a protein's function. For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis pathway,...
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis pathway,...
00:50Anaphase Promoting Complex
The stepwise destruction of specific proteins is necessary for the progression and completion of the cell cycle. Such proteins are ubiquitinated by ubiquitin ligases and then subsequently destroyed by the proteasome. The SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC) are two important ubiquitin ligases involved in cell cycle progression. While SCF is active throughout the cell cycle, APC gets activated during metaphase to anaphase transition. Cdc20 or Cdh1 binds to APC and...
01:31The Intrinsic Apoptotic Pathway
Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
01:22Amplifying Signals via Enzymatic Cascade
When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze the...
02:34Inhibition of CDK Activity
The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...