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

Chi, G.; Bohstedt, T.; Adamson, R.; Pike, A. C. W.; Shrestha, L.; Cil, O.; Anderson, M. O.; Izadiar, M.; Williams, E.; Burgess-Brown, N. A.; Elkins, J. M.; Duerr, K. L.; Sauer, D. B.

doi:10.64898/2026.11.01.757131

bioRxiv · 10.64898/2026.11.01.757131

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

Chi, G.·Bohstedt, T.·Adamson, R.·Pike, A. C. W.·Shrestha, L.·Cil, O.·Anderson, M. O.·Izadiar, M.·Williams, E.·Burgess-Brown, N. A.·Elkins, J. M.·Duerr, K. L.·Sauer, D. B.

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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.

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Chi, G., Bohstedt, T., Adamson, R., Pike, A. C. W., Shrestha, L., Cil, O., Anderson, M. O., Izadiar, M., Williams, E., Burgess-Brown, N. A., Elkins, J. M., Duerr, K. L., Sauer, D. B.. 2026-11-03. Structural Basis for Inhibition of Human Anion Transporter SLC26A6/PAT-1. https://doi.org/10.64898/2026.11.01.757131

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