The structure of mouse L1210 dihydrofolate reductase-drug complexes and the construction of a model of human enzyme.
The structure of mouse L1210 dihydrofolate reductase (DHFR) complexed with NADPH and trimethoprim has been refined at 2.0 A resolution. The analogous complex with NADPH and methotrexate has been refined at 2.5 A resolution. These structures reveal for the first time details of drug interactions with a mammalian DHFR, which are compared with those observed from previous X-ray investigations of DHFR/inhibitor complexes. The refined L1210 structure has been used as the basis for the construction of a model of the human enzyme. There are only twenty-one sequence differences between mouse L1210 and human DHFRs, and all but two of these are located close to the molecular surface: a strong indication that the active sites are essentially identical in these two mammalian enzymes.
D000818:Animals; D001665:Binding Sites; D006801:Humans; D007939:Leukemia L1210 / Q000201:enzymology*; D051379:Mice; D008958:Models, Molecular; D009249:NADP / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D013045:Species Specificity; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism*; D014295:Trimethoprim / Q000378:metabolism*; D014961:X-Ray Diffraction
D009363:Neoplasm Proteins; D009249:NADP; D014295:Trimethoprim; D013762:Tetrahydrofolate Dehydrogenase