Structural Basis of Outstanding Multivalent Effects in Jack Bean α-Mannosidase Inhibition

Multivalent design of glycosidase inhibitors is a promising strategy for the treatment of diseases involving enzymatic hydrolysis of glycosidic bonds in carbohydrates. An essential prerequisite for successful applications is the atomic‐level understanding of how outstanding binding enhancement occur...

Descripción completa

Detalles Bibliográficos
Autores principales: Howard, Eduardo Ignacio, Cousido Siah, Alexandra, Lepage, Mathieu L., Schneider, Jérémy P., Bodlenner, Anne, Mitschler, André, Meli, Alessandra, Izzo, Irene, Álvarez, Hugo Ariel, Podjarny, Alberto, Compain, Philippe
Formato: Articulo Preprint
Lenguaje:Inglés
Publicado: 2018
Materias:
Química
Cyclic peptoids
Hydrolases
Iminosugars
Multivalency
X-ray diffraction
Acceso en línea:http://sedici.unlp.edu.ar/handle/10915/96218
https://ri.conicet.gov.ar/11336/87935
http://doi.wiley.com/10.1002/anie.201801202
Aporte de:
SEDICI (UNLP) de Universidad Nacional de La Plata
Descripción
Sumario:Multivalent design of glycosidase inhibitors is a promising strategy for the treatment of diseases involving enzymatic hydrolysis of glycosidic bonds in carbohydrates. An essential prerequisite for successful applications is the atomic‐level understanding of how outstanding binding enhancement occurs with multivalent inhibitors. Herein we report the first high‐resolution crystal structures of the Jack bean α‐mannosidase (JBα‐man) in apo and inhibited states. The three‐dimensional structure of JBα‐man in complex with the multimeric cyclopeptoid‐based inhibitor displaying the largest binding enhancements reported so far provides decisive insight into the molecular mechanisms underlying multivalent effects in glycosidase inhibition.

Ejemplares similares