8BAC

Crystal structure of human heparanase in complex with competitive inhibitor GD05

This is a non-PDB format compatible entry.

Summary for 8BAC

• Entry DOI: 10.2210/pdb8bac/pdb
• Descriptor: Heparanase 50 kDa subunit, Heparanase 8 kDa subunit, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: inhibitor complex, hydrolase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 52672.48

Authors

Armstrong, Z.,Davies, G.J. (deposition date: 2022-10-11, release date: 2023-03-01, Last modification date: 2024-10-16)

Primary citation

Doherty, G.G.,Ler, G.J.M.,Wimmer, N.,Bernhardt, P.V.,Ashmus, R.A.,Vocadlo, D.J.,Armstrong, Z.,Davies, G.J.,Maccarana, M.,Li, J.P.,Kayal, Y.,Ferro, V.
Synthesis of Uronic Acid 1-Azasugars as Putative Inhibitors of alpha-Iduronidase, beta-Glucuronidase and Heparanase.
Chembiochem, 24:e202200619-e202200619, 2023

PubMed Abstract: 1-Azasugar analogues of l-iduronic acid (l-IdoA) and d-glucuronic acid (d-GlcA) and their corresponding enantiomers have been synthesized as potential pharmacological chaperones for mucopolysaccharidosis I (MPS I), a lysosomal storage disease caused by mutations in the gene encoding α-iduronidase (IDUA). The compounds were efficiently synthesized in nine or ten steps from d- or l-arabinose, and the structures were confirmed by X-ray crystallographic analysis of key intermediates. All compounds were inactive against IDUA, although l-IdoA-configured 8 moderately inhibited β-glucuronidase (β-GLU). The d-GlcA-configured 9 was a potent inhibitor of β-GLU and a moderate inhibitor of the endo-β-glucuronidase heparanase. Co-crystallization of 9 with heparanase revealed that the endocyclic nitrogen of 9 forms close interactions with both the catalytic acid and catalytic nucleophile.

PubMed: 36453606
DOI: 10.1002/cbic.202200619

Experimental method

X-RAY DIFFRACTION (2.05 Å)