Structural basis of substrate transport and drug recognition by the human thiamine transporter SLC19A3

Author:

Gabriel FlorianORCID,Spriestersbach LeaORCID,Fuhrmann Antonia,Jungnickel Katharina E. J.ORCID,Mostafavi SiavashORCID,Pardon ElsORCID,Steyaert JanORCID,Löw ChristianORCID

Abstract

AbstractThiamine (vitamin B1) functions as an essential coenzyme in cells. Humans and other mammals cannot synthesise this vitaminde novoand thus have to take it up from their diet. Eventually, every cell needs to import thiamine across its plasma membrane which is mainly mediated by two specific thiamine transporters SLC19A2 and SLC19A3. Loss of function mutations in either of these transporters leads to detrimental, life-threatening metabolic disorders. SLC19A3 is furthermore a major site of drug interactions. Many medications, including antidepressants, antibiotics and chemotherapeutics are known to inhibit this transporter, with potentially fatal consequences for patients. Despite a thorough functional characterisation over the past two decades, the structural basis of its transport mechanism and drug interactions has remained elusive. Here, we report eight cryo-electron microscopy (cryo-EM) structures of the human thiamine transporter SLC19A3 in complex with various ligands. Conformation-specific nanobodies enabled us to capture different states of SLC19A3’s transport cycle, revealing the molecular details of thiamine recognition and transport. We identified nine novel drug interactions of SLC19A3 and determined structures of the transporter in complex with the inhibitors fedratinib, hydroxychloroquine, amprolium and amitriptyline. These data allow us to develop an understanding of the transport mechanism and ligand recognition of SLC19A3.

Publisher

Cold Spring Harbor Laboratory

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3