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The structure of mouse L1210 dihydrofolate reductase‐drug complexes and the construction of a model of human enzyme
Author(s) -
Stammers D.K.,
Champness J.N.,
Beddell C.R.,
Dann J.G.,
Eliopoulos E.,
Geddes A.J.,
Ogg D.,
North A.C.T.
Publication year - 1987
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/0014-5793(87)81042-6
Subject(s) - dihydrofolate reductase , enzyme , methotrexate , biochemistry , l1210 cells , stereochemistry , biology , active site , chemistry , in vitro , immunology , cytotoxicity
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.