8CQI

Human heparanase in complex with inhibitor R3794

Summary for 8CQI

• Entry DOI: 10.2210/pdb8cqi/pdb
• Descriptor: Heparanase 50 kDa subunit, Heparanase, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (8 entities in total)
• Functional Keywords: hydrolase, glycoside hydrolase, protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 53923.91

Authors

Moran, E.M.,Davies, G.J.,Chen, C.,Nieuwendijk, E.V.,Wu, L.,Skoulikopoulou, F.,Riet, V.V.,Overkleeft, H.S.,Armstrong, Z. (deposition date: 2023-03-06, release date: 2024-01-10, Last modification date: 2024-01-24)

Primary citation

Chen, Y.,van den Nieuwendijk, A.M.C.H.,Wu, L.,Moran, E.,Skoulikopoulou, F.,van Riet, V.,Overkleeft, H.S.,Davies, G.J.,Armstrong, Z.
Molecular Basis for Inhibition of Heparanases and beta-Glucuronidases by Siastatin B.
J.Am.Chem.Soc., 146:125-133, 2024

PubMed Abstract: Siastatin B is a potent and effective iminosugar inhibitor of three diverse glycosidase classes, namely, sialidases, β--glucuronidases, and -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--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 - and -configured 3-GDIs and characterized their binding both structurally and kinetically to exo-β--glucuronidases and the anticancer target human heparanase. This revealed submicromolar inhibition of exo-β--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.

PubMed: 38118176
DOI: 10.1021/jacs.3c04162

Experimental method

X-RAY DIFFRACTION (2.1 Å)