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Published on: December 25, 2021
Crystal structure of glucokinase regulatory protein
Alexander Pautsch1, Nadja Stadler, Adelheid Löhle
1Departments of Lead Identification and Optimization Support, ‡CardioMetabolic Diseases Research, §CNS Diseases Research, ∥Drug Discovery Support, ⊥BP Process Science, and @Medicinal Chemistry, Boehringer Ingelheim Pharma GmbH & Company KG , Biberach an der Riss, Germany.
Abstract:
Glucokinase (GK) plays a major role in the regulation of blood glucose homeostasis in both the liver and the pancreas. In the liver, GK is controlled by the GK regulatory protein (GKRP). GKRP in turn is activated by fructose 6-phosphate (F6P) and inactivated by fructose 1-phosphate (F1P). Disrupting the GK-GKRP complex increases the activity of GK in the cytosol and is considered an attractive concept for the regulation of blood glucose. We have determined the crystal structure of GKRP in its inactive F1P-bound form. The binding site for F1P is located deeply buried at a domain interface, and H-D exchange experiments confirmed that F1P and F6P compete for this site. The structure of the inactive GKRP-F1P complex provides a starting point for understanding the mechanism of fructose phosphate-dependent GK regulation at an atomic level.
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