6R4K

Structure of beta-glucosidase A from Paenibacillus polymyxa complexed with a monovalent inhibitor

Summary for 6R4K

• Entry DOI: 10.2210/pdb6r4k/pdb
• Descriptor: Beta-glucosidase A, (2~{S},3~{S},4~{R})-2-[[4-[4-[2-[2-(2-azanylidenehydrazinyl)ethoxy]ethoxy]phenyl]-1,2,3-triazol-1-yl]methyl]pyrrolidine-3,4-diol (3 entities in total)
• Functional Keywords: hydrolase, beta-glucosidase, glycosidase, carbohydrate, carbohydrate metabolism, polisaccharide degradation, complex, inhibitor
• Biological source: Paenibacillus polymyxa
• Total number of polymer chains: 2
• Total formula weight: 104000.29

Authors

Jimenez-Ortega, E.,Sanz-Aparicio, J. (deposition date: 2019-03-22, release date: 2019-07-03, Last modification date: 2024-01-24)

Primary citation

Martinez-Bailen, M.,Jimenez-Ortega, E.,Carmona, A.T.,Robina, I.,Sanz-Aparicio, J.,Talens-Perales, D.,Polaina, J.,Matassini, C.,Cardona, F.,Moreno-Vargas, A.J.
Structural basis of the inhibition of GH1 beta-glucosidases by multivalent pyrrolidine iminosugars.
Bioorg.Chem., 89:103026-103026, 2019

PubMed Abstract: The synthesis of multivalent pyrrolidine iminosugars via CuAAC click reaction between different pyrrolidine-azide derivatives and tri- or hexavalent alkynyl scaffolds is reported. The new multimeric compounds, together with the monomeric reference, were evaluated as inhibitors against two homologous GH1 β-glucosidases (BglA and BglB from Paenibacillus polymyxa). The multivalent inhibitors containing an aromatic moiety in the linker between the pyrrolidine and the scaffold inhibited the octameric BglA (µM range) but did not show affinity against the monomeric BglB, despite the similarity between the active site of both enzymes. A modest multivalent effect (rp/n = 12) was detected for the hexavalent inhibitor 12. Structural analysis of the complexes between the monomeric and the trimeric iminosugar inhibitors (4 and 10) and BglA showed the insertion of the inhibitors at the active site of BglA, confirming a competitive mode of inhibition as indicated by enzyme kinetics. Additionally, structural comparison of the BglA/4 complex with the reported BglB/2F-glucose complex illustrates the key determinants responsible for the inhibitory effect and explains the reasons of the inhibition of BglA and the no inhibition of BglB. Potential inhibition of other β-glucosidases with therapeutic relevance is discussed under the light of these observations.

PubMed: 31226649
DOI: 10.1016/j.bioorg.2019.103026

Experimental method

X-RAY DIFFRACTION (2.13 Å)