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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Towards an understanding of drug resistance in malaria : three-dimensional structure of Plasmodium falciparum dihydrofolate reductase by homology building. / Lemcke, T; Christensen, I T; Jørgensen, Flemming Steen.

In: Bioorganic & Medicinal Chemistry, Vol. 7, No. 6, 1999, p. 1003-11.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Lemcke, T, Christensen, IT & Jørgensen, FS 1999, 'Towards an understanding of drug resistance in malaria: three-dimensional structure of Plasmodium falciparum dihydrofolate reductase by homology building', Bioorganic & Medicinal Chemistry, vol. 7, no. 6, pp. 1003-11. https://doi.org/10.1016/S0968-0896(99)00018-8

APA

Lemcke, T., Christensen, I. T., & Jørgensen, F. S. (1999). Towards an understanding of drug resistance in malaria: three-dimensional structure of Plasmodium falciparum dihydrofolate reductase by homology building. Bioorganic & Medicinal Chemistry, 7(6), 1003-11. https://doi.org/10.1016/S0968-0896(99)00018-8

Vancouver

Lemcke T, Christensen IT, Jørgensen FS. Towards an understanding of drug resistance in malaria: three-dimensional structure of Plasmodium falciparum dihydrofolate reductase by homology building. Bioorganic & Medicinal Chemistry. 1999;7(6):1003-11. https://doi.org/10.1016/S0968-0896(99)00018-8

Author

Lemcke, T ; Christensen, I T ; Jørgensen, Flemming Steen. / Towards an understanding of drug resistance in malaria : three-dimensional structure of Plasmodium falciparum dihydrofolate reductase by homology building. In: Bioorganic & Medicinal Chemistry. 1999 ; Vol. 7, No. 6. pp. 1003-11.

Bibtex

@article{3bdbbf79e4ed455fabfd8db4d4d0892c,
title = "Towards an understanding of drug resistance in malaria: three-dimensional structure of Plasmodium falciparum dihydrofolate reductase by homology building",
abstract = "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.",
keywords = "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",
author = "T Lemcke and Christensen, {I T} and J{\o}rgensen, {Flemming Steen}",
year = "1999",
doi = "10.1016/S0968-0896(99)00018-8",
language = "English",
volume = "7",
pages = "1003--11",
journal = "Bioorganic & Medicinal Chemistry",
issn = "0968-0896",
publisher = "Pergamon Press",
number = "6",

}

RIS

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

VL - 7

SP - 1003

EP - 1011

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

SN - 0968-0896

IS - 6

ER -

ID: 38394335