Methotrexate binds in a non‐productive orientation to human dihydrofolate reductase in solution, based on NMR spectroscopy

FEBS Letters

Stockman, Brian J.²  DeYarman, Michael T.¹  Wagner, Gerhard²  Nirmala, N.R.²  Delcamp, Tavner J.¹  Freisheim, James H.¹ 

[1] Department of Biochemistry and Molecular Biology, Medical College of Ohio, Toledo, OH 43699, USA;Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA

关键词: Dihydrofolate reductase;    Protein NMR;    Protein-drug interaction;    Methotrexate;    DHFR;    dihydrofolate reductase;    DQF-COSY;    double quantum filtered correlated spectroscopy;    NOE;    nuclear Overhauser enhancement;    NOESY;    nuclear Overhauser enhancement spectroscopy;   

DOI  :  10.1016/0014-5793(91)80604-2

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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.

【 授权许可】

Unknown