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Updated: Jul 22, 2025

Functional Characterization of Na+/H+ Exchangers of Intracellular Compartments Using Proton-killing Selection to Express Them at the Plasma Membrane
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Molecular basis for selective uptake and elimination of organic anions in the kidney by OAT1

Joanne L Parker1,2, Takafumi Kato3,4, Gabriel Kuteyi5,6

  • 1Department of Biochemistry, University of Oxford, Oxford, UK. joanne.parker@bioch.ox.ac.uk.

Nature Structural & Molecular Biology
|July 23, 2023
PubMed

Insights

Researchers revealed the kidney

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Nephrology

Background:

  • Kidneys maintain blood homeostasis by regulating toxins, drugs, and metabolites.
  • Organic anion transporters (OATs) in nephrons handle metabolite/toxin recognition and urinary excretion.
  • OAT inhibition is a therapeutic strategy to enhance drug efficacy and mitigate kidney toxicity.

Purpose of the Study:

  • To elucidate the mechanisms of metabolite cycling, drug transport, and intracellular chloride regulation in OAT1.
  • To understand how α-ketoglutarate (α-KG) drives organic anion transport and how chloride allosterically regulates OAT1.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) to determine the structures of OAT1.
  • OAT1 structures were determined in complex with α-ketoglutarate (α-KG), tenofovir, and probenecid.
  • In vivo cellular assays were employed to validate functional aspects.

Main Results:

  • Provided high-resolution cryo-EM structures of OAT1 bound to α-KG, tenofovir, and probenecid.
  • Explained the molecular basis for α-KG-driven drug elimination via OAT1.
  • Elucidated the allosteric regulation of OAT1 by intracellular chloride.

Conclusions:

  • OAT1 utilizes α-KG export to drive selective transport of organic anions, including drugs.
  • Intracellular chloride acts as an allosteric regulator of OAT1 function.
  • These findings provide molecular insights into renal organic anion transport and its regulation.

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