Publication: Crystal structure of dihydrofolate reductase from Plasmodium vivax: Pyrimethamine displacement linked with mutation-induced resistance
Issued Date
2005-09-13
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ISSN
00278424
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2-s2.0-24944558791
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Mahidol University
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SCOPUS
Bibliographic Citation
Proceedings of the National Academy of Sciences of the United States of America. Vol.102, No.37 (2005), 13046-13051
Suggested Citation
Palangpon Kongsaeree, Puttapol Khongsuk, Ubolsree Leartsakulpanich, Penchit Chitnumsub, Bongkoch Tarnchompoo, Malcolm D. Walkinshaw, Yongyuth Yuthavong Crystal structure of dihydrofolate reductase from Plasmodium vivax: Pyrimethamine displacement linked with mutation-induced resistance. Proceedings of the National Academy of Sciences of the United States of America. Vol.102, No.37 (2005), 13046-13051. doi:10.1073/pnas.0501747102 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/17201
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Title
Crystal structure of dihydrofolate reductase from Plasmodium vivax: Pyrimethamine displacement linked with mutation-induced resistance
Abstract
Pyrimethamine (Pyr) targets dihydrofolate reductase of Plasmodium vivax (PvDHFR) as well as other malarial parasites, but its use as antimalarial is hampered by the widespread high resistance. Comparison of the crystal structures of PvDHFR from wild-type and the Pyr-resistant (SP21, Ser-58 → Arg + Ser-117 → Asn) strain as complexes with NADPH and Pyr or its analog lacking p-CI (Pyr20) clearly shows that the steric conflict arising from the side chain of Asn-117 in the mutant enzyme, accompanied by the loss of binding to Ser-120, is mainly responsible for the reduction in binding of Pyr. Pyr20 still effectively inhibits both the wild-type and SP21 proteins, and the x-ray structures of these complexes show how Pyr20 fits into both active sites without steric strain. These structural insights suggest a general approach for developing new generations of antimalarial DHFR inhibitors that, by only occupying substrate space of the active site, would retain binding affinity with the mutant enzymes. © 2005 by The National Academy of Sciences of the USA.