Towards an understanding of drug resistance in malaria: three-dimensional structure of Plasmodium falciparum dihydrofolate reductase by homology building

Research output: Contribution to journalJournal articleResearchpeer-review

T Lemcke, I T Christensen, Flemming Steen Jørgensen

A three-dimensional (3-D) model of dihydrofolate reductase (DHFR) from Plasmodium falciparum has been constructed by homology building. The model building has been based on a structural alignment of five X-ray structures of DHFR from different species. The 3-D model of the plasmodial DHFR was obtained by amino acid substitution in the human DHFR, which was chosen as template, modification of four loops (two insertions, two deletions) and subsequent energy minimization. The active site of P. falciparum DHFR was analyzed and compared to human DHFR with respect to sequence variations and structural differences. Based on this analysis the molecular consequences of point mutations known to be involved in drug resistance were discussed. The significance of the most important point mutation causing resistance, S108N, could be explained by the model, whereas the point mutations associated with enhanced resistance, N51I and C59R, seem to have a more indirect effect on inhibitor binding.
Original languageEnglish
JournalBioorganic & Medicinal Chemistry
Volume7
Issue number6
Pages (from-to)1003-11
Number of pages9
ISSN0968-0896
DOIs
Publication statusPublished - 1999

    Research areas

  • Amino Acid Sequence, Animals, Binding Sites, Crystallography, X-Ray, Drug Resistance, Folic Acid Antagonists, Humans, Malaria, Falciparum, Models, Molecular, Molecular Sequence Data, Plasmodium falciparum, Protein Conformation, Sequence Alignment, Sequence Homology, Amino Acid, Tetrahydrofolate Dehydrogenase

ID: 38394335