Dihydrofolate reductase. The stereochemistry of inhibitor selectivity.
X-ray structural results are reported for 10 triazine and pyrimidine inhibitors of dihydrofolate reductase, each one studied as a ternary complex with NADPH and chicken dihydrofolate reductase. Analysis of these data and comparison with structural results from the preceding paper (Matthews, D.A., Bolin, J.T., Burridge, J.M., Filman, D.J., Volz, K.W., Kaufman, B. T., Beddell, C.R., Champness, J.N., Stammers, D.K., and Kraut, J. (1985) J. Biol. Chem. 260, 381-391) in which we contrasted binding of the antibiotic trimethoprim (TMP) to chicken dihydrofolate reductase on the one hand with its binding to Escherichia coli dihydrofolate reductase on the other, permit identification of differences that are important in accounting for TMP's selectivity. The crystallographic evidence strongly suggests that loss of a potential hydrogen bond between the 4-amino group of TMP and the backbone carbonyl of Val-115 when TMP binds to chicken dihydrofolate reductase but not when it binds to the E. coli reductase is the major factor responsible for this drug's more potent inhibition of bacterial dihydrofolate reductase. A key finding of the current study which is important in understanding why TMP binds differently to chicken and E. coli dihydrofolate reductases is that residues on opposite sides of the active-site cleft in chicken dihydrofolate reductase are about 1.5-2.0 A further apart than are structurally equivalent residues in the E. coli enzyme.
D000818:Animals; D002645:Chickens; D004926:Escherichia coli / Q000201:enzymology; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D013045:Species Specificity; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000302:isolation & purification; D014961:X-Ray Diffraction
D005493:Folic Acid Antagonists; D013762:Tetrahydrofolate Dehydrogenase