pH-tuneable binding of 2′-phospho-ADP-ribose to ketopantoate reductase: A structural and calorimetric study

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Abstract

The crystal structure of Escherichia coli ketopantoate reductase in complex with 2'-monophosphoadenosine 5'-diphosphoribose, a fragment of NADP+ that lacks the nicotinamide ring, is reported. The ligand is bound at the enzyme active site in the opposite orientation to that observed for NADP+, with the adenine ring occupying the lipophilic nicotinamide pocket. Isothermal titration calorimetry with R31A and N98A mutants of the enzyme is used to show that the unusual ;reversed binding mode' observed in the crystal is triggered by changes in the protonation of binding groups at low pH. This research has important implications for fragment-based approaches to drug design, namely that the crystallization conditions and the chemical modification of ligands can have unexpected effects on the binding modes.

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Ciulli, A., Lobley, C. M. C., Tuck, K. L., Smith, A. G., Blundell, T. L., & Abell, C. (2007). pH-tuneable binding of 2′-phospho-ADP-ribose to ketopantoate reductase: A structural and calorimetric study. Acta Crystallographica Section D: Biological Crystallography, 63(2), 171–178. https://doi.org/10.1107/S0907444906044465

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