Molecular basis for selective uptake and elimination of organic anions in the kidney by OAT1.

Autor: Parker JL; Department of Biochemistry, University of Oxford, Oxford, UK. joanne.parker@bioch.ox.ac.uk.; The Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK. joanne.parker@bioch.ox.ac.uk., Kato T; Department of Biochemistry, University of Oxford, Oxford, UK. takafumi.kato@bioch.ox.ac.uk.; The Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK. takafumi.kato@bioch.ox.ac.uk., Kuteyi G; Department of Biochemistry, University of Oxford, Oxford, UK.; The Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK., Sitsel O; Department of Biochemistry, University of Oxford, Oxford, UK.; Max Planck Institute of Biochemistry, Max Planck Institute of Molecular Physiology, Dortmund, Germany., Newstead S; Department of Biochemistry, University of Oxford, Oxford, UK. simon.newstead@bioch.ox.ac.uk.; The Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK. simon.newstead@bioch.ox.ac.uk.
Jazyk: angličtina
Zdroj: Nature structural & molecular biology [Nat Struct Mol Biol] 2023 Nov; Vol. 30 (11), pp. 1786-1793. Date of Electronic Publication: 2023 Jul 23.
DOI: 10.1038/s41594-023-01039-y
Abstrakt: In mammals, the kidney plays an essential role in maintaining blood homeostasis through the selective uptake, retention or elimination of toxins, drugs and metabolites. Organic anion transporters (OATs) are responsible for the recognition of metabolites and toxins in the nephron and their eventual urinary excretion. Inhibition of OATs is used therapeutically to improve drug efficacy and reduce nephrotoxicity. The founding member of the renal organic anion transporter family, OAT1 (also known as SLC22A6), uses the export of α-ketoglutarate (α-KG), a key intermediate in the Krebs cycle, to drive selective transport and is allosterically regulated by intracellular chloride. However, the mechanisms linking metabolite cycling, drug transport and intracellular chloride remain obscure. Here, we present cryogenic-electron microscopy structures of OAT1 bound to α-KG, the antiviral tenofovir and clinical inhibitor probenecid, used in the treatment of Gout. Complementary in vivo cellular assays explain the molecular basis for α-KG driven drug elimination and the allosteric regulation of organic anion transport in the kidney by chloride.
(© 2023. The Author(s).)
Databáze: MEDLINE
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