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

T Lemcke; I T Christensen; Flemming Steen Jørgensen

doi:10.1016/S0968-0896(99)00018-8

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

T Lemcke, I T Christensen, Flemming Steen Jørgensen

52 Citations (Scopus)

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.

Original language	English
Journal	Bioorganic & Medicinal Chemistry
Volume	7
Issue number	6
Pages (from-to)	1003-11
Number of pages	9
ISSN	0968-0896
DOIs	https://doi.org/10.1016/S0968-0896(99)00018-8
Publication status	Published - 1999

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/S0968-0896(99)00018-8

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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

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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.",

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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

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DO - 10.1016/S0968-0896(99)00018-8

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SN - 0968-0896

VL - 7

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EP - 1011

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

IS - 6

ER -

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

Abstract

Keywords

UN SDGs

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