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Structures and membrane interactions of human OAT1 in complex with clinical used drugs

Xuening Wu1, Yongbo Luo2, Shijian Feng1

  • 1Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, Sichuan 610044, China.

Science Advances
|February 14, 2025
PubMed

Insights

Structural insights into human organic anion transporter 1 (hOAT1) reveal how it recognizes diverse drugs. Cryo-EM structures show drug binding sites, explaining polyspecific anionic drug recognition and informing therapeutic strategies.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Pharmacology

Background:

  • Organic anion transporters (OATs) are crucial for renal excretion of organic compounds.
  • OAT1 significantly impacts drug pharmacokinetics and interactions.
  • The structural basis for hOAT1's broad substrate recognition remains unclear.

Purpose of the Study:

  • To determine the molecular structure of human OAT1 (hOAT1).
  • To elucidate the structural basis of polyspecific anionic drug recognition by hOAT1.
  • To provide insights into therapeutic inhibition strategies for OATs.

Main Methods:

  • Cryogenic electron microscopy (cryo-EM) was used to determine the structures of hOAT1.
  • Complex structures of hOAT1 with cidofovir and glibenclamide were obtained.

Main Results:

  • The study presents cryo-EM structures of hOAT1 in complex with cidofovir and glibenclamide.
  • Both drugs bind to a central site, revealing inward-facing conformations of the transporter.
  • Specific residues within the central site explain the binding of diverse inhibitors.

Conclusions:

  • The structures provide a molecular understanding of hOAT1 drug recognition.
  • This work offers a structural basis for designing OAT1 inhibitors and understanding drug interactions.
  • Findings advance the therapeutic modulation of OAT-mediated substrate elimination or retention.

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