Solution structure of human dihydrofolate reductase in its complex with trimethoprim and NADPH.
نویسندگان
چکیده
Nadezhda V. Kovalevskaya, Yegor D. Smurnyy, Vladimir I. Polshakov, Berry Birdsall, Alan F. Bradbury, Tom Frenkiel & James Feeney* Center for Drug Chemistry, 119815 Moscow, Russia; Center for Magnetic Tomography and Spectroscopy, M.V. Lomonosov Moscow State University, 119992 Moscow, Russia; Division of Molecular Structure, National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7 1AA, U.K.; MRC Biomedical NMR Centre, National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7 1AA, U.K.
منابع مشابه
Characterization of rates of ring-flipping in trimethoprim in its ternary complexes with Lactobacillus casei dihydrofolate reductase and coenzyme analogues.
NMR measurements have been used to investigate rates of ring-flipping and the activation parameters for the trimethoxybenzyl ring of the antibacterial drug trimethoprim (TMP) bound to Lactobacillus casei dihydrofolate reductase (DHFR) for a series of ternary complexes formed with analogues of the coenzyme NADPH. Rates were obtained at several temperatures from line shape analyses ((13)C-edited ...
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R67 dihydrofolate reductase (DHFR) catalyzes the reduction of dihydrofolate (DHF) to tetrahydrofolate using NADPH as a cofactor. This enzyme is a homotetramer possessing 222 symmetry, and a single active site pore traverses the length of the protein. A promiscuous binding surface can accommodate either DHF or NADPH, thus two nonproductive complexes can form (2NADPH or 2DHF) as well as a product...
متن کاملNMR Structures of Apo L. casei Dihydrofolate Reductase and Its Complexes with Trimethoprim and NADPH: Contributions to Positive Cooperative Binding from Ligand-Induced Refolding, Conformational Changes, and Interligand Hydrophobic Interactions
In order to examine the origins of the large positive cooperativity (ΔG(0)(coop) = -2.9 kcal mol(-1)) of trimethoprim (TMP) binding to a bacterial dihydrofolate reductase (DHFR) in the presence of NADPH, we have determined and compared NMR solution structures of L. casei apo DHFR and its binary and ternary complexes with TMP and NADPH and made complementary thermodynamic measurements. The DHFR ...
متن کاملDihydrofolate reductase from trimethoprim-resistant Escherichia coli MB 3746 and MB 3747. Purification, amino acid composition, and some kinetic properties.
Dihydrofolate reductase has been isolated and purified to homogeneity in g6od yield from two trimethoprim-resistant strains of Escherichia coli K12, strains MB 3746 and MB 3747. The two enzymes are closely related to one another and to the dihydrofolate reductase from E. coli MB 1428. The 3746 and 3747 reductases both exhibit an apparent molecular weight of 17,500 with almost identical amino ac...
متن کاملModulation of specific binding of Lactobacillus casei dihydrofolate reductase to DNA by folinic acid.
Dihydrofolate reductase (DHFR) plays an essential role in intermediary metabolism, catalysing the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate, the latter serving as a carrier of onecarbon fragments in the biosynthesis of amino acids, thymidylate and purines [ 11. DHFR has been the subject of intense investigations as it is the target of important anti-bacterial and anti-neopl...
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ورودعنوان ژورنال:
- Journal of biomolecular NMR
دوره 33 1 شماره
صفحات -
تاریخ انتشار 2005