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-Structure paper
タイトル | Structural basis of the substrate recognition and inhibition mechanism of Plasmodium falciparum nucleoside transporter PfENT1. |
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ジャーナル・号・ページ | Nat Commun, Vol. 14, Issue 1, Page 1727, Year 2023 |
掲載日 | 2023年3月28日 |
著者 | Chen Wang / Leiye Yu / Jiying Zhang / Yanxia Zhou / Bo Sun / Qingjie Xiao / Minhua Zhang / Huayi Liu / Jinhong Li / Jialu Li / Yunzi Luo / Jie Xu / Zhong Lian / Jingwen Lin / Xiang Wang / Peng Zhang / Li Guo / Ruobing Ren / Dong Deng / |
PubMed 要旨 | By lacking de novo purine biosynthesis enzymes, Plasmodium falciparum requires purine nucleoside uptake from host cells. The indispensable nucleoside transporter ENT1 of P. falciparum facilitates ...By lacking de novo purine biosynthesis enzymes, Plasmodium falciparum requires purine nucleoside uptake from host cells. The indispensable nucleoside transporter ENT1 of P. falciparum facilitates nucleoside uptake in the asexual blood stage. Specific inhibitors of PfENT1 prevent the proliferation of P. falciparum at submicromolar concentrations. However, the substrate recognition and inhibitory mechanism of PfENT1 are still elusive. Here, we report cryo-EM structures of PfENT1 in apo, inosine-bound, and inhibitor-bound states. Together with in vitro binding and uptake assays, we identify that inosine is the primary substrate of PfENT1 and that the inosine-binding site is located in the central cavity of PfENT1. The endofacial inhibitor GSK4 occupies the orthosteric site of PfENT1 and explores the allosteric site to block the conformational change of PfENT1. Furthermore, we propose a general "rocker switch" alternating access cycle for ENT transporters. Understanding the substrate recognition and inhibitory mechanisms of PfENT1 will greatly facilitate future efforts in the rational design of antimalarial drugs. |
リンク | Nat Commun / PubMed:36977719 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 3.11 - 4.04 Å |
構造データ | EMDB-32618, PDB-7wn0: EMDB-32619, PDB-7wn1: EMDB-33756, PDB-7ydq: |
化合物 | ChemComp-NOS: ChemComp-IRX: |
由来 |
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キーワード | TRANSPORT PROTEIN / malaria / nucleoside transporter / Equilibrative nucleoside transporter / inosine / MEMBRANE PROTEIN / GSK4 |