The structure of mouse L1210 dihydrofolate reductase-drug complexes and the construction of a model of human enzyme |
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| Authors: | D K Stammers J N Champness C R Beddell J G Dann E Eliopoulos A J Geddes D Ogg A C North |
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| Institution: | 1. Wellcome Research Laboratories, Beckenham, BR3 3BS England;2. Astbury Department of Biophysics, University of Leeds, Leeds LS2 9JT, England |
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| Abstract: | 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. |
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