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Lecture

L(SB)2 Seminar: Discovering new heparanase inhibitors through X-ray Crystallography

Date
Thursday 21 November 2024
Time
Location
Gorlaeus Building
Einsteinweg 55
2333 CC Leiden
Room
CM.1.26

We would like to invite you to a new seminar series that aims to bring together all researchers in Leiden that are interested in biophysics and structural biology. L(SB)2, the Leiden Seminars in Biophysics and Structural Biology, takes place monthly and combines presentations of talented PhD students from Leiden University with talks of PIs from other Dutch or international universities. We hope to see many of you there!

Abstract

Siastatin B is a potent and effective iminosugar inhibitor of three diverse glycosidase classes, namely, sialidases, β-D-glucuronidases, and N-acetyl-glucosaminidases. The mode of inhibition of glucuronidases, in contrast to sialidases, has long been enigmatic as siastatin B appears too bulky and incorrectly substituted to be accommodated within a β-D-glucuronidase active site pocket. Herein, we show through crystallographic analysis of protein-inhibitor complexes that siastatin B generates both a hemiaminal and a 3-geminal diol iminosugar (3-GDI) that are, rather than the parent compound, directly responsible for enzyme inhibition. The hemiaminal product is the first observation of a natural product that belongs to the noeuromycin class of inhibitors. Additionally, the 3-GDI represents a new and potent class of the iminosugar glycosidase inhibitor. To substantiate our findings, we synthesized both the gluco- and galacto-configured 3-GDIs and characterized their binding both structurally and kinetically to exo-β-D-glucuronidases and the anticancer target human heparanase. This revealed submicromolar inhibition of exo-β-D-glucuronidases and an unprecedented binding mode by this new class of inhibitor. Our results reveal the mechanism by which siastatin B acts as a broad-spectrum glycosidase inhibitor, identify a new class of glycosidase inhibitor, and suggest new functionalities that can be incorporated into future generations of glycosidase inhibitors. 

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