Dihydrofolate reductase structure

Hopfinger, A. J. (1981) Inhibition of dihydrofolate reductase structure-activity correlations of 2,4-diamino-5-benzylpyrimidines based upon molecular shape analysis. J. Med. Chem. 24, 818-822. 

Battershell, C., Malhotra, D. and Hopfinger, A.J. (1981). Inhibition of Dihydrofolate Reductase Structure-Activity Correlations of Quinazolines Based upon Molecular Shape Analysis. 

Fukunaga, J.Y., Hansch, C. and Steller, E.E. (1976). Inhibition of Dihydrofolate Reductase. Structure-Activity Correlations of Quinazolines. J.Med.Chem., 19, 605-611. 

T A and H Kalayeh 1991. Applications of Neural Networks in Quantitative Structure-Activity ationships of Dihydrofolate Reductase Inhibitors, journal of Medicinal Chemistry 34 2824-2836. ik M and R C Glen 1992. Applications of Rule-induction in the Derivation of Quantitative icture-Activity Relationships. Journal of Computer-Aided Molecular Design 6 349-383. 

GM Crippen. Quantitative structure-activity relationships by distance geometry Systematic analysis of dihydrofolate reductase inhibitors. I Med Chem 23 599-606, 1980. 

TA Andrea, H Kalayeh. Applications of neural networks in quantitative structure-activity relationships of dihydrofolate reductase inhibitors. J Med Chem 34 2824-2836, 1991. 

FIGURE 18.35 Formation of THF from folic acid by the dihydrofolate reductase reaction. The R group on these folate molecules symbolizes the one to seven (or more) glutamate units that folates characteristically contain. All of these glutamates are bound in y-carboxyl amide linkages (as in the folic acid structure shown in the box A Deeper Look Folic Acid, Pterins, and Insect VFingis). The one-carbon units carried by THF are bound at N, or at or as a single carbon attached to both... 

A review is given of the application of Molecular Dynamics (MD) computer simulation to complex molecular systems. Three topics are treated in particular the computation of free energy from simulations, applied to the prediction of the binding constant of an inhibitor to the enzyme dihydrofolate reductase the use of MD simulations in structural refinements based on two-dimensional high-resolution nuclear magnetic resonance data, applied to the lac repressor headpiece the simulation of a hydrated lipid bilayer in atomic detail. The latter shows a rather diffuse structure of the hydrophilic head group layer with considerable local compensation of charge density. 

Matthews DA, Alden RA, Bolin JT, Filman DJ, Freer ST, Hamlin R, Hoi WG, Kisliuk RL, Pastore EJ, Plante FT, Xuong N, Kraut J. Dihydrofolate reductase from Lactobacillus casei. X-ray structure of the enzyme methotrexate-NADPH complex. J Biol Chem 1978 253 6946-54. 

Hirst JD. Nonlinear quantitative structure-activity relationship for the inhibition of dihydrofolate reductase by pyrimidines. J Med Chem 1996 39(18) 3526-32. 

Gschwend DA, Sirawaraporn W, Santi DV, Kuntz ID. Specificity in structure-based drug design identification of a novel, selective inhibitor of Pneumocystis carinii dihydrofolate reductase. Proteins Struct Funct Genet 1997 29 59-67. 

Wyss PC, Gerber P, Hartman PG, Hubschwerlen C, Locher H, Marty HP, Stahl M. Novel dihydrofolate reductase inhibitors. Structure-based versus diversity-based library design and high-throughput synthesis and screening. J Med Chem 2003 46 2304-12. 

Bowden K., Harris N.V. Watson C.A. (1993) Structure-activity relationships of dihydrofolate reductase inhihitors. / Chemother, 5, 377-388. 

The author assumed that the Born radii of atoms can be estimated from the solvent exposure factors for sampling spheres around the atoms. Two spheres were used in a five-parameter equahon to calculate the Born radii. The parameters of the equahon were eshmated using numerical calculahons from X-ray protein structures for dihydrofolate reductase. In addition to AGol the author also considered the AGJ term accounting for cavity formahon and dispersion of the solute-solvent interactions as ... 

Figure 1.4 Left panel Space filing model of the structure of bacterial dihydrofolate reductase with methotrexate bound to the active site. Right panel Close-up view of the active site, illustrating the structural complementarity between the ligand (methotrexate) and the binding pocket. See color insert. Source Courtesy of Nesya Nevins.

Figure 1.4 Top panel Space filing model of the structure of bacterial dihydrofolate reductase with...

The dihydrofolate reductase enzyme (DHFR) is involved in one-carbon metabolism and is required for the survival of prokaryotic and eukaryotic cells. The enzyme catalyzes the reduction of dihydrofolate to tetrahydrofolate, which is required for the biosynthesis of serine, methionine, purines, and thymidylate. The mouse dihydrofolate reductase (mDHFR) is a small (21 kD), monomeric enzyme that is highly homologous to the E. coli enzyme (29% identify) (Pelletier et al., 1998). The three-dimensional structure of DHFR indicates that it is comprised of three structural fragments F[l], F[2] andF[3] (Gegg etal., 1997). 

Hagler, Structure and energetics of ligand binding to proteins Escherichia coli dihydrofolate reductase-trimethoprim, a drug-receptor system, Proteins 4 31 (1988). 

Poe, K. Williams, and K. Hoogsteen, Dihydrofolate reductase X-ray structure of the binary complex with methotrexate, Science 197 452 (1977). 

Crystal structures of escherichia coli and lactobacillus casei dihydrofolate reductase refined at 1.7A resolution, J. Biol. Chem. 257 13663 (1982). 

Kraut, Crystal structures of recombinant dihydrofolate reductase complexed with folate and 5-deazafolate, Biochemistry 29 9467 (1990). 

R. Beddell, J. N. Champness, D. K. Stammers, and J. Kraut, Refined crystal structure of Escherichia coli and chicken liver dihydrofolate reductase containing bound trimethoprim, J. Biol. Chem. 260 381 (1985). 

Dihydrofolate reductases (DHFR), 48, 54, 56 Dimethyl chalcogenides, 131-133 Dimethylselenide, 131-133 Dimethyltellurides, 131-133 Diorgano diselenides, 113 Diorgano ditellurides, 113 Diorganochalcogen(IV) dihalides crystallographic structure, 80f redox reactions, 90 Diorganoselenides... 

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