Division of Obstetrics, Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, Chengdu, China.
Hefei National Laboratory for Physical Sciences at Microscale, CAS Centre for Excellence in Molecular Cell Science, School of Life Sciences, University of Science and Technology of China, Hefei, China.
PLoS Biol. 2020 Aug 10;18(8):e3000790. doi: 10.1371/journal.pbio.3000790. eCollection 2020 Aug.
Concentrative nucleoside transporters (CNTs), members of the solute carrier (SLC) 28 transporter family, facilitate the salvage of nucleosides and therapeutic nucleoside derivatives across the plasma membrane. Despite decades of investigation, the structures of human CNTs remain unknown. We determined the cryogenic electron microscopy (cryo-EM) structure of human CNT (hCNT) 3 at an overall resolution of 3.6 Å. As with its bacterial homologs, hCNT3 presents a trimeric architecture with additional N-terminal transmembrane helices to stabilize the conserved central domains. The conserved binding sites for the substrate and sodium ions unravel the selective nucleoside transport and distinct coupling mechanism. Structural comparison of hCNT3 with bacterial homologs indicates that hCNT3 is stabilized in an inward-facing conformation. This study provides the molecular determinants for the transport mechanism of hCNTs and potentially facilitates the design of nucleoside drugs.
集中核苷转运蛋白(CNTs)是溶质载体(SLC)28 转运蛋白家族的成员,可促进核苷和治疗性核苷衍生物穿过质膜进行回收。尽管经过了几十年的研究,人类 CNT 的结构仍然未知。我们确定了人类 CNT(hCNT)3 的低温电子显微镜(cryo-EM)结构,整体分辨率为 3.6 Å。与细菌同源物一样,hCNT3 呈现出三聚体结构,并增加了额外的 N 端跨膜螺旋以稳定保守的中央结构域。用于底物和钠离子的保守结合位点揭示了选择性核苷转运和独特的偶联机制。hCNT3 与细菌同源物的结构比较表明,hCNT3 稳定在向内打开的构象。这项研究为 hCNTs 的转运机制提供了分子决定因素,并可能促进核苷药物的设计。