8ohr

Crystal structure of human heparanase in complex with glucuronic acid configured 3-geminal diol iminosugar inhibitor

spinqualitylabelsall models 8ohr, resolution 1.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8ohr is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.8Å Ligands: CL, EDO, NAG, VP5 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Siastatin B is a potent and effective iminosugar inhibitor of three diverse glycosidase classes, namely, sialidases, beta-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 beta-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-beta-d-glucuronidases and the anticancer target human heparanase. This revealed submicromolar inhibition of exo-beta-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. Molecular Basis for Inhibition of Heparanases and beta-Glucuronidases by Siastatin B.,Chen Y, van den Nieuwendijk AMCH, Wu L, Moran E, Skoulikopoulou F, van Riet V, Overkleeft HS, Davies GJ, Armstrong Z J Am Chem Soc. 2024 Jan 10;146(1):125-133. doi: 10.1021/jacs.3c04162. Epub 2023 , Dec 20. PMID:38118176 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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