6m20

Crystal structure of Plasmodium falciparum hexose transporter PfHT1 bound with glucose

spinqualitylabelsall models 6m20, resolution 2.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.6Å Ligands: BGC, BNG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed 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 A in complex with D-glucose and 3.7 A 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. Structural Basis for Blocking Sugar Uptake into the Malaria Parasite Plasmodium falciparum.,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 JW, Yan C, Kato N, Yin H, Yan N Cell. 2020 Aug 20. pii: S0092-8674(20)31006-0. doi: 10.1016/j.cell.2020.08.015. PMID:32860739 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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