8B0D
Crystal structure of beta-glucuronidase from Acidobacterium capsulatum in complex with covalent inhibitor VB151
This is a non-PDB format compatible entry.
Summary for 8B0D
| Entry DOI | 10.2210/pdb8b0d/pdb |
| Descriptor | beta-glucuronidase from Acidobacterium capsulatum, ALANINE, (1~{S},2~{R},3~{R},4~{S},6~{S})-2-(2-acetamidoethoxy)-3,4,6-tris(oxidanyl)cyclohexane-1-carboxylic acid, ... (5 entities in total) |
| Functional Keywords | b-glucuronidase, hydrolase |
| Biological source | Acidobacterium capsulatum |
| Total number of polymer chains | 1 |
| Total formula weight | 51276.99 |
| Authors | Armstrong, Z.,Davies, G.J. (deposition date: 2022-09-07, release date: 2022-12-28, Last modification date: 2024-10-16) |
| Primary citation | Borlandelli, V.,Armstrong, Z.,Nin-Hill, A.,Codee, J.D.C.,Raich, L.,Artola, M.,Rovira, C.,Davies, G.J.,Overkleeft, H.S. 4-O-Substituted Glucuronic Cyclophellitols are Selective Mechanism-Based Heparanase Inhibitors. Chemmedchem, 18:e202200580-e202200580, 2023 Cited by PubMed Abstract: Degradation of the extracellular matrix (ECM) supports tissue integrity and homeostasis, but is also a key factor in cancer metastasis. Heparanase (HPSE) is a mammalian ECM-remodeling enzyme with β-D-endo-glucuronidase activity overexpressed in several malignancies, and is thought to facilitate tumor growth and metastasis. By this virtue, HPSE is considered an attractive target for the development of cancer therapies, yet to date no HPSE inhibitors have progressed to the clinic. Here we report on the discovery of glucurono-configured cyclitol derivatives featuring simple substituents at the 4-O-position as irreversible HPSE inhibitors. We show that these compounds, unlike glucurono-cyclophellitol, are selective for HPSE over β-D-exo-glucuronidase (GUSB), also in platelet lysate. The observed selectivity is induced by steric and electrostatic interactions of the substituents at the 4-O-position. Crystallographic analysis supports this rationale for HPSE selectivity, and computer simulations provide insights in the conformational preferences and binding poses of the inhibitors, which we believe are good starting points for the future development of HPSE-targeting antimetastatic cancer drugs. PubMed: 36533564DOI: 10.1002/cmdc.202200580 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.62 Å) |
Structure validation
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