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The substrate and inhibitor binding mechanism of polyspecific transporter OAT1 revealed by high-resolution cryo-EM

Tongyi Dou1,2, Tengfei Lian1, Shi Shu1

  • 1Laboratory of Membrane Proteins and Structural Biology, Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute, Bethesda, MD, USA.

Nature Structural & Molecular Biology
|October 16, 2023
PubMed

Insights

Organic anion transporters (OATs) are vital for kidney function and drug interactions. New cryo-EM structures reveal a conserved mechanism for how these SLC22 transporters bind diverse compounds.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Organic anion transporters (OATs) from the SLC22 family are critical for transporting metabolites and drugs.
  • OATs play a role in kidney function, drug metabolism, and drug-drug interactions.
  • Understanding OAT substrate binding is essential for drug development and predicting toxicity.

Purpose of the Study:

  • To elucidate the molecular basis of substrate and inhibitor binding in OATs.
  • To determine the cryo-EM structures of rat OAT1 (SLC22A6) in complex with substrates.
  • To reveal the conserved binding mechanism across SLC22 transporters.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) was used to determine high-resolution structures.
  • Structures were solved for rat OAT1 alone and in complex with para-aminohippuric acid and probenecid.
  • Analysis of the protein-ligand interactions to understand substrate binding.

Main Results:

  • The cryo-EM structures of rat OAT1 were determined at resolutions of 2.1–2.9 Å.
  • A conserved substrate binding mechanism involving four aromatic residues forming a cage was identified.
  • This cage structure accommodates the binding of diverse organic anions.

Conclusions:

  • The identified binding mechanism is conserved across SLC22 transporters.
  • These findings provide structural insights into OAT substrate specificity and drug interactions.
  • This knowledge can inform the design of new drugs targeting OATs.

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