Structural basis for prostaglandin and drug transport via SLCO2A1

  • Nat Commun. 2026 Mar 20;17(1):2285. doi: 10.1038/s41467-026-70227-3.
Chitra Joshi  #  1  2 ,  Justin C Deme  #  3 ,  Yoshinobu Nakamura  #  4  5 ,  Wei-Tse Hsu  #  1  6 ,  Jonathan D Goult  1  2 ,  Takafumi Kato  1  2 ,  Joanne L Parker  1  2 ,  Philip C Biggin  7  8 ,  Susan M Lea  9  10 ,  Takeo Nakanishi  11 ,  Simon Newstead  12  13
Affiliations
  • 1. Department of Biochemistry, University of Oxford, Oxford, UK.
  • 2. Kavli Institute of Nanoscience Discovery, University of Oxford, Oxford, UK.
  • 3. Center for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
  • 4. Faculty of Pharmacy, Takasaki University of Health and Welfare, Takasaki, Gunma, Japan.
  • 5. Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
  • 6. Structural Bioinformatics and Computational Biochemistry, University of Oxford, Oxford, UK.
  • 7. Department of Biochemistry, University of Oxford, Oxford, UK. [email protected].
  • 8. Structural Bioinformatics and Computational Biochemistry, University of Oxford, Oxford, UK. [email protected].
  • 9. Center for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA. [email protected].
  • 10. Structural Biology, St Jude Children's Research Hospital, Memphis, TN, USA. [email protected].
  • 11. Faculty of Pharmacy, Takasaki University of Health and Welfare, Takasaki, Gunma, Japan. [email protected].
  • 12. Department of Biochemistry, University of Oxford, Oxford, UK. [email protected].
  • 13. Kavli Institute of Nanoscience Discovery, University of Oxford, Oxford, UK. [email protected].
  • # Contributed equally.
PMID: 41862483 DOI: 10.1038/s41467-026-70227-3
Abstract

Organic anion-transporting polypeptide transporters (SLCO/OATPs) function as cellular gatekeepers, regulating intestinal absorption, hepatic and renal clearance, and the tissue distribution of drugs and metabolites in the human body. However, the mechanisms underlying substrate selection within the SLCO superfamily remain unclear, hampering efforts to rationalize the interaction of drugs and metabolites with these transporters. SLCO2A1 (also known as OATP2A1) is responsible for the distribution of eicosanoids, including prostaglandins (PGs) and thromboxanes, throughout the body, in addition to several families of nonsteroidal anti-inflammatory drugs (NSAIDs). Here, we present cryogenic electron microscopy structures of SLCO2A1 bound to endogenous PGs and to four widely prescribed medications for treating inflammation, chronic asthma, and Parkinson's disease (PD). Complementary molecular dynamics and in vivo cellular assays elucidate the molecular basis for PG and drug recognition. Our study reports essential mechanistic details that underpin substrate selection and subfamily adaptation within the broader SLCO superfamily of drug and metabolite transporters.

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