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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.


Journal article



Publication Date





178 - 184


Animals, Binding Sites, Humans, Leukemia L1210, Mice, Models, Molecular, NADP, Neoplasm Proteins, Protein Binding, Protein Conformation, Species Specificity, Tetrahydrofolate Dehydrogenase, Trimethoprim, X-Ray Diffraction