Cryo-EM structures of the human NaS1 and NaDC1 transporters revealed the elevator transport and allosteric regulation mechanism

Chi, Ximin1,2; Chen, Yiming3; Li, Yaning2,4,5; Dai, Lu4; Zhang, Yuanyuan2; Shen, Yaping2; Chen, Yun2,6; Shi, Tianhao4; Yang, Haonan4; Wang, Zilong3; Yan, Renhong4

2024-03-29

10.1126/sciadv.adl3685

SCIENCE ADVANCES   影响因子和分区

2375-2548

The solute carrier 13 (SLC13) family comprises electrogenic sodium ion-coupled anion cotransporters, segregating into sodium ion-sulfate cotransporters (NaSs) and sodium ion-di- and-tricarboxylate cotransporters (NaDCs). NaS1 and NaDC1 regulate sulfate homeostasis and oxidative metabolism, respectively. NaS1 deficiency affects murine growth and fertility, while NaDC1 affects urinary citrate and calcium nephrolithiasis. Despite their importance, the mechanisms of substrate recognition and transport remain insufficiently characterized. In this study, we determined the cryo-electron microscopy structures of human NaS1, capturing inward-facing and combined inward-facing/outward-facing conformations within a dimer both in apo and sulfate-bound states. In addition, we elucidated NaDC1's outward-facing conformation, encompassing apo, citrate-bound, and N-(p-amylcinnamoyl) anthranilic acid (ACA) inhibitor-bound states. Structural scrutiny illuminates a detailed elevator mechanism driving conformational changes. Notably, the ACA inhibitor unexpectedly binds primarily anchored by transmembrane 2 (TM2), Loop 10, TM11, and TM6a proximate to the cytosolic membrane. Our findings provide crucial insights into SLC13 transport mechanisms, paving the way for future drug design.

SCI ; EI

英语

通讯

Major Talent Recruitment Program of Guangdong Province[2021QNO2Y167] ; National Natural Science Foundation of China["82202517","32371267","82101297","32100975"]

Science & Technology - Other Topics

Multidisciplinary Sciences

WOS:001194882400020

AMER ASSOC ADVANCEMENT SCIENCE

Web of Science

1.Xiamen Univ, Innovat Ctr Cell Signaling Network, Sch Life Sci, State Key Lab Cellular Stress Biol, Xiamen 361102, Fujian, Peoples R China
2.Westlake Univ, Key Lab Struct Biol Zhejiang Prov, Westlake Lab Life Sci & Biomed, Ctr Infect Dis Res,Sch Life Sci, Hangzhou 310024, Zhejiang, Peoples R China
3.Southern Univ Sci & Technol, Key Univ Lab Metab & Hlth Guangdong, Sch Med, Dept Med Neurosci, Shenzhen 518055, Guangdong, Peoples R China
4.Southern Univ Sci & Technol, Key Univ Lab Metab & Hlth Guangdong, Inst Biol Electron Microscopy, Sch Med,Dept Biochem, Shenzhen 518055, Guangdong, Peoples R China
5.Tsinghua Univ, Beijing Adv Innovat Ctr Struct Biol, Tsinghua Peking Joint Ctr Life Sci, Sch Life Sci, Beijing 100084, Peoples R China
6.Novoprot Sci Inc, Suzhou 215000, Peoples R China

Chi, Ximin,Chen, Yiming,Li, Yaning,et al. Cryo-EM structures of the human NaS1 and NaDC1 transporters revealed the elevator transport and allosteric regulation mechanism[J]. SCIENCE ADVANCES,2024,10(13).

Chi, Ximin.,Chen, Yiming.,Li, Yaning.,Dai, Lu.,Zhang, Yuanyuan.,...&Yan, Renhong.(2024).Cryo-EM structures of the human NaS1 and NaDC1 transporters revealed the elevator transport and allosteric regulation mechanism.SCIENCE ADVANCES,10(13).

Chi, Ximin,et al."Cryo-EM structures of the human NaS1 and NaDC1 transporters revealed the elevator transport and allosteric regulation mechanism".SCIENCE ADVANCES 10.13(2024).