Structural basis for prostaglandin and drug transport via SLCO2A1

Authors:
Open Access
Publisher website
Google Scholar
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.
Funding Information
  • Wellcome (215519/Z/19/Z)
  • Wellcome (219531/Z/19/Z)
  • Wellcome (219531/Z/19/Z)
  • Biotechnology and Biological Sciences Research Council (BB/Z517215/1)
  • Biotechnology and Biological Sciences Research Council (BB/Z517215/1)
  • Japan Society for the Promotion of Science (22K15295)
  • Japan Society for the Promotion of Science (24K09819)
  • Engineering and Physical Sciences Research Council (EP/X035603/1)
  • Engineering and Physical Sciences Research Council (EP/X035603/1)

This publication has 85 references indexed in Scilit: