6M20

Crystal structure of Plasmodium falciparum hexose transporter PfHT1 bound with glucose

Summary for 6M20

• Entry DOI: 10.2210/pdb6m20/pdb
• Descriptor: Hexose transporter 1, beta-D-glucopyranose, nonyl beta-D-glucopyranoside, ... (4 entities in total)
• Functional Keywords: mfs, hexose transporter, occluded state, plasmodium falciparum, transport protein
• Biological source: Plasmodium falciparum
• Total number of polymer chains: 4
• Total formula weight: 230576.96

Authors

Jiang, X.,Yuan, Y.Y.,Zhang, S.,Wang, N.,Yan, C.Y.,Yan, N. (deposition date: 2020-02-26, release date: 2020-09-09, Last modification date: 2024-10-16)

Primary citation

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.
Structural Basis for Blocking Sugar Uptake into the Malaria Parasite Plasmodium falciparum.
Cell, 183:258-268.e12, 2020

PubMed Abstract: 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.

PubMed: 32860739
DOI: 10.1016/j.cell.2020.08.015

Experimental method

X-RAY DIFFRACTION (2.6 Å)