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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.

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Department of Integrative Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, UdS, 1 rue Laurent Fries, 67404, Illkirch CEDEX, France.
Instituto de Física de Líquidos y Sistemas Biológicos, CONICET, UNLP, Calle 59 No. 789, La Plata, Argentina.
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.
Department of Chemistry and Biology "A. Zambelli", University of Salerno, Via Giovanni Paolo II, 132, 84084, Fisciano, Salerno, Italy.


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.


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

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