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Methotrexate binds in a non‐productive orientation to human dihydrofolate reductase in solution, based on NMR spectroscopy
Author(s) -
Stockman Brian J.,
Nirmala N.R.,
Wagner Gerhard,
Delcamp Tavner J.,
DeYarman Michael T.,
Freisheim James H.
Publication year - 1991
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(91)80604-2
Subject(s) - dihydrofolate reductase , methotrexate , chemistry , nuclear magnetic resonance spectroscopy , enzyme , intracellular , stereochemistry , spectroscopy , crystallography , biochemistry , biology , physics , quantum mechanics , immunology
Dihydrofolate reductase (DHFR) is an intracellular target enzyme for folate antagonist drugs, including methotrexatte. In order to compare the binding of methotrexate to human DHFR in solution with that observed in the crystalline state, NMR spectroscopy has been used to determine the conformation of the drug bound to human DHFR in solution. In agreement with what has been observed in the crystalline state, NOE's identified protein and methotrexate protons indicate that methotrexate binds in a non‐productive orientation. In contrast to what has been reported for E. coli DHFR in solution, only one bound conformation of methotrexate is observed.