期刊
ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS
卷 71, 期 -, 页码 553-559出版社
INT UNION CRYSTALLOGRAPHY
DOI: 10.1107/S2053230X15000989
关键词
dihydroorotate dehydrogenase; Plasmodium falciparum; DSM59
资金
- US Department of Energy, Office of Biological and Environmental Research [DE-AC02-06CH11357]
- United States National Institutes of Health [U01AI075594, R01AI103947, R01 AI099280]
- Welch Foundation [I-1257]
Plasmodium species are protozoan parasites that are the causative agent of malaria. Malaria is a devastating disease, and its treatment and control have been hampered by the propensity of the parasite to become drug-resistant. Dihydroorotate dehydrogenase (DHODH) has been identified as a promising new target for the development of antimalarial agents. Here, the X-ray structure of P. falciparum DHODH bound to a potent and selective N-phenylbenzamide-based inhibitor (DSM59) is described at 2.3 angstrom resolution. The structure elucidates novel binding-site interactions and shows how conformational flexibility of the enzyme leads to the ability to bind diverse chemical structures with high affinity. This information provides new insight into the design of high-affinity DHODH inhibitors for the treatment of malaria.
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