NIH Research Festival
Organic anion transporters (OATs) of the SLC22 family play critical roles in the transport of organic anions, including metabolites and therapeutic drugs, and in the transporter-mediated drug-drug interactions. Likely, OATs mediate the elimination of metabolic waste products and xenobiotics through the kidney, while OATs accumulating toxic compounds can also result in kidney failure. Moreover, OATs are important drug targets, as their inhibition can modulate the elimination or retention of substrates linked to diseases or treatments. Despite extensive research on OATs, the molecular basis of substrate and inhibitor binding has been hindered by the lack of structural information. Here, we report the cryo-electron microscopy structures of rat OAT1 (Rn-SLC22A6) and its complexes with substrate para-aminohippuric acid and inhibitor probenecid (a drug used in the treatment of chronic gout) at 2.1, 2.8, and 2.9 √Ö resolution, respectively. Our findings reveal a highly conserved mechanism for substrate and inhibitor binding in the SLC22 transporters, wherein four aromatic residues form a cage to accommodate the polyspecific binding of diverse compounds.
Scientific Focus Area: Structural Biology
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