Structure of physiological dimer of bifunctional Plasmodium falciparum dihydrofolate reductase–thymidylate synthase (DHFR-TS) shows that DHFR domains (lime green and white transparent), whose active sites are the target of antifolate antimalarial drugs, are only attached to TS domains (blue and light blue) and not involved in the dimerization. Earlier studies on antifolate resistance associated with mutations in the DHFR active site using the recombinant DHFR-only construct were limited by its aggregation at ∼2 mg/ml. Protein engineering attempts reported here have increased the protein solubility to over 13 mg/ml by mutations in a loop unique to Plasmodium species (orange). For details, see Japrung et al., pages 457–464.
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