Crystallographic investigation of the cooperative interaction between trimethoprim, reduced cofactor and dihydrofolate reductase.
The structure of the complex between E. coli (RT500) form I dihydrofolate reductase, the antibacterial trimethoprim and NADPH has been determined by X-ray crystallography. The inhibitor and cofactor are in mutual contact. A flexible chain segment which includes Met 20 is in contact with the inhibitor in the presence of NADPH, but more distant in its absence. By contrast, the inhibitor conformation is little changed with NADPH present. We discuss these observations with regard to the mutually cooperative binding of these ligands to the protein, and to the associated enhancement of inhibitory selectivity shown by trimethoprim for bacterial as opposed to vertebrate enzyme.
Champness
J N
JN
Stammers
D K
DK
Beddell
C R
CR
D001665:Binding Sites; D004926:Escherichia coli / Q000201:enzymology; D007780:Lacticaseibacillus casei / Q000201:enzymology; D008958:Models, Molecular; D009249:NADP / Q000378:metabolism*; D011487:Protein Conformation; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism*; D014295:Trimethoprim / Q000378:metabolism*; D014961:X-Ray Diffraction
D009249:NADP; D014295:Trimethoprim; D013762:Tetrahydrofolate Dehydrogenase