Abstract
Dihydrofolate reductase is the site of action of the ‘anti-folate’ drugs, such as methotrexate, pyrimethamine and trimethoprim, which act as competitive inhibitors of the enzyme1–3. These inhibitors bind to the Lactobacillus casei enzyme cooperatively with the coenzyme NADP(H), which can increase inhibitor binding by as much as 700-fold4. The existence of conformational changes accompanying ligand binding and involved in inhibitor–coenzyme cooperativity has been inferred from NMR experiments4–9. It seems likely that these conformational changes are important in determining the specificity of the enzyme for its ligands4,10,11. We now report the direct observation by NMR of two distinct conformations of the enzyme–trimethoprim–NADP+ ternary complex in solution.
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Gronenborn, A., Birdsall, B., Hyde, E. et al. Direct observation by NMR of two coexisting conformations of an enzyme–ligand complex in solution. Nature 290, 273–274 (1981). https://doi.org/10.1038/290273a0
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DOI: https://doi.org/10.1038/290273a0
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