BACKGROUND: Glycogen phosphorylases catalyze the breakdown of glycogen to glucose-1-phosphate for glycolysis. Maintaining control of blood glucose levels is critical in minimizing the debilitating effects of diabetes, making liver glycogen phosphorylase a potential therapeutic target. RESULTS: The binding site in human liver glycogen phosphorylase (HLGP) for a class of promising antidiabetic agents was identified crystallographically. The site is novel and functions allosterically by stabilizing the inactive conformation of HLGP. The initial view of the complex revealed key structural information and inspired the design of a new class of inhibitors which bind with nanomolar affinity and whose crystal structure is also described. CONCLUSIONS: We have identified the binding site of a new class of allosteric HLGP inhibitors. The crystal structure revealed the details of inhibitor binding, led to the design of a new class of compounds, and should accelerate efforts to develop therapeutically relevant molecules for the treatment of diabetes.
BACKGROUND:Glycogen phosphorylases catalyze the breakdown of glycogen to glucose-1-phosphate for glycolysis. Maintaining control of blood glucose levels is critical in minimizing the debilitating effects of diabetes, making liver glycogen phosphorylase a potential therapeutic target. RESULTS: The binding site in human liver glycogen phosphorylase (HLGP) for a class of promising antidiabetic agents was identified crystallographically. The site is novel and functions allosterically by stabilizing the inactive conformation of HLGP. The initial view of the complex revealed key structural information and inspired the design of a new class of inhibitors which bind with nanomolar affinity and whose crystal structure is also described. CONCLUSIONS: We have identified the binding site of a new class of allosteric HLGP inhibitors. The crystal structure revealed the details of inhibitor binding, led to the design of a new class of compounds, and should accelerate efforts to develop therapeutically relevant molecules for the treatment of diabetes.
Authors: Alexey A Zeifman; Victor S Stroylov; Fedor N Novikov; Oleg V Stroganov; Alexandra L Zakharenko; Svetlana N Khodyreva; Olga I Lavrik; Ghermes G Chilov Journal: J Mol Model Date: 2011-11-09 Impact factor: 1.810
Authors: S Freeman; J B Bartlett; G Convey; I Hardern; J L Teague; S J G Loxham; J M Allen; S M Poucher; A D Charles Journal: Br J Pharmacol Date: 2006-10-03 Impact factor: 8.739
Authors: Lilla Nagy; Judit Márton; András Vida; Gréta Kis; Éva Bokor; Sándor Kun; Mónika Gönczi; Tibor Docsa; Attila Tóth; Miklós Antal; Pál Gergely; Balázs Csóka; Pal Pacher; László Somsák; Péter Bai Journal: Br J Pharmacol Date: 2017-06-18 Impact factor: 8.739
Authors: Evangelia D Chrysina; Magda N Kosmopoulou; Constantinos Tiraidis; Rozina Kardakaris; Nicolas Bischler; Demetres D Leonidas; Zsuzsa Hadady; Laszlo Somsak; Tibor Docsa; Pal Gergely; Nikos G Oikonomakos Journal: Protein Sci Date: 2005-03-01 Impact factor: 6.725
Authors: S M Poucher; S Freeman; S J G Loxham; G Convey; J B Bartlett; J De Schoolmeester; J Teague; M Walker; A V Turnbull; A D Charles; F Carey; S Berg Journal: Br J Pharmacol Date: 2007-10-15 Impact factor: 8.739