TY - JOUR
T1 - Towards an understanding of drug resistance in malaria
T2 - three-dimensional structure of Plasmodium falciparum dihydrofolate reductase by homology building
AU - Lemcke, T
AU - Christensen, I T
AU - Jørgensen, Flemming Steen
PY - 1999
Y1 - 1999
N2 - 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.
AB - 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.
KW - Amino Acid Sequence
KW - Animals
KW - Binding Sites
KW - Crystallography, X-Ray
KW - Drug Resistance
KW - Folic Acid Antagonists
KW - Humans
KW - Malaria, Falciparum
KW - Models, Molecular
KW - Molecular Sequence Data
KW - Plasmodium falciparum
KW - Protein Conformation
KW - Sequence Alignment
KW - Sequence Homology, Amino Acid
KW - Tetrahydrofolate Dehydrogenase
U2 - 10.1016/S0968-0896(99)00018-8
DO - 10.1016/S0968-0896(99)00018-8
M3 - Journal article
C2 - 10428368
SN - 0968-0896
VL - 7
SP - 1003
EP - 1011
JO - Bioorganic & Medicinal Chemistry
JF - Bioorganic & Medicinal Chemistry
IS - 6
ER -
