Your browser doesn't support javascript.
loading
Structure-based design and mechanisms of allosteric inhibitors for mitochondrial branched-chain α-ketoacid dehydrogenase kinase.
Proc Natl Acad Sci U S A ; 110(24): 9728-33, 2013 Jun 11.
Article en En | MEDLINE | ID: mdl-23716694
ABSTRACT
The branched-chain amino acids (BCAAs) leucine, isoleucine, and valine are elevated in maple syrup urine disease, heart failure, obesity, and type 2 diabetes. BCAA homeostasis is controlled by the mitochondrial branched-chain α-ketoacid dehydrogenase complex (BCKDC), which is negatively regulated by the specific BCKD kinase (BDK). Here, we used structure-based design to develop a BDK inhibitor, (S)-α-chloro-phenylpropionic acid [(S)-CPP]. Crystal structures of the BDK-(S)-CPP complex show that (S)-CPP binds to a unique allosteric site in the N-terminal domain, triggering helix movements in BDK. These conformational changes are communicated to the lipoyl-binding pocket, which nullifies BDK activity by blocking its binding to the BCKDC core. Administration of (S)-CPP to mice leads to the full activation and dephosphorylation of BCKDC with significant reduction in plasma BCAA concentrations. The results buttress the concept of targeting mitochondrial BDK as a pharmacological approach to mitigate BCAA accumulation in metabolic diseases and heart failure.
Asunto(s)
Palabras clave

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Proteínas Quinasas / Estructura Terciaria de Proteína / Proteínas Mitocondriales / Inhibidores de Proteínas Quinasas Límite: Animals Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2013 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Proteínas Quinasas / Estructura Terciaria de Proteína / Proteínas Mitocondriales / Inhibidores de Proteínas Quinasas Límite: Animals Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2013 Tipo del documento: Article País de afiliación: Estados Unidos