Download MendeleyEvidence for the Quercetin Binding Site of Glycogen Phosphorylase as a Target for Liver-Isoform-Selective Inhibitors against Glioblastoma: Investigation of Flavanols Epigallocatechin Gallate and Epigallocatechin.
Alexopoulos, S., McGawley, M., Mathews, R., Papakostopoulou, S., Koulas, S., Leonidas, D.D., Zwain, T., Hayes, J.M., Skamnaki, V.(2024) J Agric Food Chem 72: 24070-24081
- PubMed: 39433280
- DOI: https://doi.org/10.1021/acs.jafc.4c06920
- Primary Citation of Related Structures:
8QMU, 8R52, 8R53, 8R6V - PubMed Abstract:
Glycogen phosphorylase (GP) is the rate-determining enzyme in glycogenolysis, and its druggability has been extensively studied over the years for the development of therapeutics against type 2 diabetes (T2D) and, more recently, cancer. However, the conservation of binding sites between the liver and muscle isoforms makes the inhibitor selectivity challenging. Using a combination of kinetic, crystallographic, modeling, and cellular studies, we have probed the binding of dietary flavonoids epigallocatechin gallate (EGCG) and epigallocatechin (EGC) to GP isoforms. The structures of rmGPb-EGCG and rmGPb-EGC complexes were determined by X-ray crystallography, showing binding at the quercetin binding site (QBS) in agreement with kinetic studies that revealed both compounds as noncompetitive inhibitors of GP, with EGCG also causing a significant reduction in cell viability and migration of U87-MG glioblastoma cells. Interestingly, EGCG exhibits different binding modes to GP isoforms, revealing QBS as a promising site for GP targeting, offering new opportunities for the design of liver-selective GP inhibitors.
Organizational Affiliation:
Department of Biochemistry and Biotechnology, University of Thessaly, Biopolis, Larisa 41500, Greece.
