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Dr. Brian Miller

Florida State University

Department of Chemistry and Biochemistry

October 5th, 2018 – Fall Seminar

Time and Location: Noon in Meyerhoff Chemistry, Room 120

Host: Dr. Songon An

Glucokinase (GCK) is the central regulator of glucose homeostasis in the human body. It also serves as the prototypic example of an emerging class of proteins with allosteric-like behavior that originates from intrinsic polypeptide dynamics, rather than from long-distance communication between multiple ligand binding sites. A major impediment to understanding the molecular origins of allostery in non-conventional systems such as glucokinase is the lack of a detailed picture of the protein’s dynamic conformational landscape, including the number, structure and relative population of states encoded by the protein’s amino acid sequence. Here, using a combination of X-ray crystallography, high-resolution NMR, fluorescence spectroscopy, H/D exchange mass spectrometry and chemical quench flow kinetics, we investigate the dynamic functional landscape of human glucokinase. Our results reveal how conformational heterogeneity of the enzyme gives rise to allostery and how the functional landscape is altered by non-cooperative variants that cause the human disease congenital hyperinsulinemia. These findings may facilitate the development of new diabetes therapeutics that preferentially target specific conformational states within the enzyme’s unliganded ensemble.