Structural Basis for Inhibition of Human Anion Transporter SLC26A6/PAT-1
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…
The human anion transporter PAT-1, also known as SLC26A6, is a crucial protein responsible for the exchange of small organic and inorganic anions such as oxalate and chloride in the kidney and intestines. Mutations in the gene encoding PAT-1 have been linked to conditions like nephrolithiasis and hyperoxaluria. Furthermore, understanding and manipulating PAT-1 could potentially lead to new therapeutic strategies for cystic fibrosis.
Researchers have already discovered two small-molecule inhibitors targeting PAT-1: DIDS, a general anion exchanger inhibitor, and PAT1inh-B01, a highly specific inhibitor.
In this study, the authors present the high-resolution cryo-electron microscopy structures of the human PAT-1 homodimer when bound to these inhibitors. These structures reveal the distinct inhibition mechanisms employed by DIDS and PAT1inh-B01. Moreover, the findings shed light on the intricate interactions between various domains of PAT-1, including the transmembrane, STAS, and N-terminal regions.
This understanding of the complex interplay between these domains and the inhibitors provides valuable insights into the molecular function of PAT-1. Ultimately, this research contributes significantly to our comprehension of SLC26 transport mechanisms and offers a deeper mechanistic understanding of PAT-1.
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