1J3J: Double Mutant (C59r+s108n) Plasmodium Falciparum Dihydrofolate Reductase-Thymidylate Synthase (Pfdhfr-Ts) Complexed With Pyrimethamine, Nadph, And Dump

Citation:
Abstract
Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) is an important target of antimalarial drugs. The efficacy of this class of DHFR-inhibitor drugs is now compromised because of mutations that prevent drug binding yet retain enzyme activity. The crystal structures of PfDHFR-TS from the wild type (TM4/8.2) and the quadruple drug-resistant mutant (V1/S) strains, in complex with a potent inhibitor WR99210, as well as the resistant double mutant (K1 CB1) with the antimalarial pyrimethamine, reveal features for overcoming resistance. In contrast to pyrimethamine, the flexible side chain of WR99210 can adopt a conformation that fits well in the active site, thereby contributing to binding. The single-chain bifunctional PfDHFR-TS has a helical insert between the DHFR and TS domains that is involved in dimerization and domain organization. Moreover, positively charged grooves on the surface of the dimer suggest a function in channeling of substrate from TS to DHFR active sites. These features provide possible approaches for the design of new drugs to overcome antifolate resistance.
PDB ID: 1J3JDownload
MMDB ID: 22577
PDB Deposition Date: 2003/2/3
Updated in MMDB: 2012/11
Experimental Method:
x-ray diffraction
Resolution: 2.3  Å
Source Organism:
Similar Structures:
Biological Unit for 1J3J: tetrameric; determined by author and by software (PISA)
Molecular Components in 1J3J
Label Count Molecule
Proteins (4 molecules)
2
Bifunctional Dihydrofolate Reductase-thymidylate Synthase
Molecule annotation
2
Bifunctional Dihydrofolate Reductase-thymidylate Synthase
Molecule annotation
Chemicals (6 molecules)
1
2
2
2
3
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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