Title | Structural Basis for Blocking Sugar Uptake into the Malaria Parasite Plasmodium falciparum. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | Jiang, X, Yuan, Y, Huang, J, Zhang, S, Luo, S, Wang, N, Pu, D, Zhao, N, Tang, Q, Hirata, K, Yang, X, Jiao, Y, Sakata-Kato, T, Wu, J-W, Yan, C, Kato, N, Yin, H, Yan, N |
Journal | Cell |
Volume | 183 |
Issue | 1 |
Pagination | 258-268.e12 |
Date Published | 2020 Oct 01 |
ISSN | 1097-4172 |
Keywords | Amino Acid Sequence, Animals, Antimalarials, Biological Transport, Glucose, Humans, Malaria, Malaria, Falciparum, Monosaccharide Transport Proteins, Parasites, Plasmodium falciparum, Protozoan Proteins, Sugars |
Abstract | <p>Plasmodium species, the causative agent of malaria, rely on glucose for energy supply during blood stage. Inhibition of glucose uptake thus represents a potential strategy for the development of antimalarial drugs. Here, we present the crystal structures of PfHT1, the sole hexose transporter in the genome of Plasmodium species, at resolutions of 2.6 Å in complex with D-glucose and 3.7 Å with a moderately selective inhibitor, C3361. Although both structures exhibit occluded conformations, binding of C3361 induces marked rearrangements that result in an additional pocket. This inhibitor-binding-induced pocket presents an opportunity for the rational design of PfHT1-specific inhibitors. Among our designed C3361 derivatives, several exhibited improved inhibition of PfHT1 and cellular potency against P. falciparum, with excellent selectivity to human GLUT1. These findings serve as a proof of concept for the development of the next-generation antimalarial chemotherapeutics by simultaneously targeting the orthosteric and allosteric sites of PfHT1.</p> |
DOI | 10.1016/j.cell.2020.08.015 |
Alternate Journal | Cell |
PubMed ID | 32860739 |