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Angew Chem Int Ed Engl. 2018 Jul 2;57(27):8002-8006. doi: 10.1002/anie.201801202. Epub 2018 Jun 6.

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

Author information

1
Department of Integrative Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, UdS, 1 rue Laurent Fries, 67404, Illkirch CEDEX, France.
2
Instituto de Física de Líquidos y Sistemas Biológicos, CONICET, UNLP, Calle 59 No. 789, La Plata, Argentina.
3
Laboratoire d'Innovation Moléculaire et Applications, Université de Strasbourg|, Université de Haute-Alsace|, CNRS|, LIMA (UMR 7042), Equipe de Synthèse Organique et Molécules Bioactives (SYBIO), ECPM, 25 rue Becquerel, 67000, Strasbourg, France.
4
Department of Chemistry and Biology "A. Zambelli", University of Salerno, Via Giovanni Paolo II, 132, 84084, Fisciano, Salerno, Italy.

Abstract

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.

KEYWORDS:

X-ray diffraction; cyclic peptoids; hydrolases; iminosugars; multivalency

PMID:
29722924
DOI:
10.1002/anie.201801202
[Indexed for MEDLINE]

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