The studies on substrate, product and inhibitor binding to a wild-type and neuronopathic form of human acid-β-glucosidase

Abstract

Gaucher disease is a lysosomal storage disorder caused by deficiency of human acid beta-glucosidase. Recent x-ray structural elucidation of the enzyme alone and in the presence of its inhibitor was done, which provided an excellent template for further studies on the binding of substrate, product and inhibitor. To draw correlations between the clinical manifestation of the disease driven by point mutations, L444P and L444R, and the placement and function of putative S-binding sites, the presented theoretical studies were undertaken, which comprised of molecular dynamics and molecular docking methods. The obtained results indicate the D443 and D445 residues as extremely important for physiological functionality of an enzyme. They also show, although indirectly, that binding of the substrate is influenced by an interplay of E235 and E334 residues, constituting putative substrate binding site, and the region flanked by D435 and D445 residues.

Mechanism of glucocerebrosidase activation and dysfunction in Gaucher disease unraveled by molecular dynamics and deep learning

“…Second, there is no structural information on how the GCase-SAPC complex interacts with the membrane. In separate studies, selected mutants have been modeled through moleculardynamics (MD) simulations (29,30), but these studies lack information on the GCase-SAPC interface, specifically, membrane Significance Gaucher disease is a rare genetic disorder that has crippling health consequences. Mutations in the GBA1 gene are known to disrupt the enzyme glucocerebrosidase-1, but it is not known, at atom-level detail, as to how enzyme function is lost.…”