What is it about?

Inhibitors of the enzyme ketohexokinase are promising drug candidates for the treatment of cardiometabolic diseases. We solved high resolution crystal structures of this enzyme from two species (human and mouse) both in unliganded states and in complex with a species- and isoform-selective ligand. Our analysis revealed a previously unrecognized hotspot for inhibitor design.

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Why is it important?

Known ketohexokinase inhibitors are not isoform selective, that is they cannot distinguish between the two related enzymes KHK-A and KHK-C. Studies with KHK-A knockout mice, however, suggest that a selective inhibitor of KHK-C could be a better way to block fructose-associated metabolic syndrome as compared to an unselective compound. In our present work we characterize and explain a small molecule inhibitor with inverse selectivity that binds more potently to KHK-A compared to KHK-C.


Learnings from our study can now be used to design ligands with the desired selectivity profile. Ultimately with the goal to provide a safer and more efficacious treatment to patients.

Alexander Pautsch
Boehringer Ingelheim Pharma

Read the Original

This page is a summary of: Crystal structures of human and mouse ketohexokinase provide a structural basis for species- and isoform-selective inhibitor design, Acta Crystallographica Section D Structural Biology, September 2023, International Union of Crystallography,
DOI: 10.1107/s2059798323006137.
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