Structural Basis for Inhibition of Human Anion Transporter SLC26A6/PAT-1

Abstract

PAT-1, encoded by the gene SLC26A6, is an exchanger of small organic and inorganic anions including oxalate and chloride in the kidney and the intestines. PAT-1 dysfunction is implicated in nephrolithiasis and hyperoxaluria, and its modulation is a potential therapeutic strategy to treat cystic fibrosis. PAT-1 has two small molecule inhibitors: DIDS, a non-specific anion exchanger inhibitor; and PAT1inh-B01 which is highly specific to PAT-1. In this study, we report high-resolution cryo-electron microscopy structures of the human PAT-1 homodimer in complex with these inhibitors to reveal their different inhibition mechanisms. These structures also uncover the complex interactions between the transmembrane, STAS and N-terminal domains, with implications on its ion exchange function. Hence, this study provides mechanistic insight into PAT-1 molecular function and inhibition, and contributes to our understanding of SLC26 transport mechanisms.