Estudios científicos
Crystal structure of death-associated protein kinase 1 in complex with the dietary compound resveratrol.
Abstract:
Death-associated protein kinase 1 (DAPK1) is a large multidomain protein with an N-terminal serine/threonine protein kinase domain. DAPK1 is considered to be a promising molecular target for the treatment of Alzheimer’s disease (AD). In the present study, the inhibitory potency of resveratrol (RSV), a dietary polyphenol found in red wine, against the catalytic activity of DAPK1 was investigated. Kinetic and fluorescent probe competitive binding analyses revealed that RSV directly inhibited the catalytic activity of DAPK1 by binding to the ATP-binding site. Crystallographic analysis of DAPK1 in complex with RSV revealed that the A-ring of RSV occupied the nucleobase-binding position. Determination of the binding mode provided a structural basis for the design of more potent DAPK1 inhibitors. In conclusion, the data here clearly show that RSV is an ATP-competitive inhibitor of DAPK1, encouraging speculation that RSV may be useful for the development of AD inhibitors.
Comentarios divulgativos:
El resveratrol es un compuesto polifenólico que se encuentra en uvas, cacahuetes, frutos rojos, y en el vino. La proteína quinasa 1 asociada a la muerte (DAPK1) es una proteína que se considera una diana molecular prometedora para el tratamiento de la enfermedad de Alzheimer. El propósito de este artículo es estudiar el efecto inhibidor del resveratrol sobre la actividad catalítica de DAPK1.
Está demostrado que el resveratrol inhibe directamente la actividad catalítica de DAPK1 al unirse al sitio de unión del ATP. Estos resultados muestran que el resveratrol es un inhibidor de ATP competitivo de DAPK1. Los datos actuales permiten un mayor conocimiento sobre el potencial del resveratrol para el tratamiento de enfermedades relacionadas con DAPK1.
