The structure of mouse L1210 dihydrofolate reductase-drug complexes and the construction of a model of human enzyme

• Published in: FEBS letters 1987-06, Vol.218 (1), p.178-184
• Main Authors: Stammers, D.K., Champness, J.N., Beddell, C.R., Dann, J.G., Eliopoulos, E., Geddes, A.J., Ogg, D., North, A.C.T.
• Format: Article
• Language: English
• Subjects: Animals; Binding Sites; Biological and medical sciences; Crystal structure; Crystalline structure; Dihydrofolate reductase; Drug-enzyme interaction; Fundamental and applied biological sciences. Psychology; Humans; Leukemia L1210 - enzymology; man; Mice; Models, Molecular; Molecular biophysics; NADP - metabolism; Neoplasm Proteins - metabolism; Protein Binding; Protein Conformation; Species Specificity; Structure in molecular biology; Tetrahydrofolate Dehydrogenase - metabolism; Trimethoprim - metabolism; X-ray crystallography; X-Ray Diffraction
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/0014-5793(87)81042-6

The structure of mouse L1210 dihydrofolate reductase (DHFR) complexed with NADPH and trimethoprim has been refined at 2.0 Å resolution. The analogous complex with NADPH and methotrexate has been refined at 2.5 Å 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.