6M2L

Crystal structure of Plasmodium falciparum hexose transporter PfHT1 bound with C3361

6M2L の概要

• エントリーDOI: 10.2210/pdb6m2l/pdb
• 関連するPDBエントリー: 6M20
• 分子名称: Hexose transporter 1, (2S,3R,4S,5R,6R)-6-(hydroxymethyl)-4-undec-10-enoxy-oxane-2,3,5-triol (2 entities in total)
• 機能のキーワード: mfs, hexose transporter, inhibitor, plasmodium falciparum, transport protein
• 由来する生物種: Plasmodium falciparum
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 113601.47

構造登録者

Jiang, X.,Yuan, Y.Y.,Zhang, S.,Wang, N.,Yan, C.Y.,Yan, N. (登録日: 2020-02-27, 公開日: 2020-09-09, 最終更新日: 2024-11-13)

主引用文献

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

実験手法

X-RAY DIFFRACTION (3.7 Å)