8ome
Crystal structure of hKHK-A in complex with compound-4
Structural highlights
DiseaseKHK_HUMAN Defects in KHK are the cause of fructosuria (FRUCT) [MIM:229800. Benign defect of intermediary metabolism.[1] [2] FunctionPublication Abstract from PubMedA molecular understanding of the proteins involved in fructose metabolism is essential for controlling the current spread of fructose-related obesity, diabetes and related adverse metabolic states in Western populations. Fructose catabolism starts with the phosphorylation of D-fructose to fructose 1-phosphate by ketohexokinase (KHK). KHK exists in two alternatively spliced isoforms: the hepatic and intestinal isoform KHK-C and the peripheral isoform KHK-A. Here, the structure of apo murine KHK (mKHK), which differs from structures of human KHK in overall conformation, is reported. An isoform-selective ligand, which offers a 50-fold higher potency on mKHK and human KHK-A compared with KHK-C, is further characterized. In mKHK, large-scale conformational changes are observed upon ligand binding. The structures suggest a combined strategy for the design of species- and isoform-selective KHK inhibitors. Crystal structures of human and mouse ketohexokinase provide a structural basis for species- and isoform-selective inhibitor design.,Ebenhoch R, Bauer M, Romig H, Gottschling D, Kley JT, Heine N, Weber A, Uphues I, Nar H, Pautsch A Acta Crystallogr D Struct Biol. 2023 Oct 1. doi: 10.1107/S2059798323006137. PMID:37712434[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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