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Title | The substrate and inhibitor binding mechanism of polyspecific transporter OAT1 revealed by high-resolution cryo-EM. |
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Journal, issue, pages | Nat Struct Mol Biol, Vol. 30, Issue 11, Page 1794-1805, Year 2023 |
Publish date | Oct 16, 2023 |
Authors | Tongyi Dou / Tengfei Lian / Shi Shu / Yi He / Jiansen Jiang / |
PubMed Abstract | Organic anion transporters (OATs) of the SLC22 family have crucial roles in the transport of organic anions, including metabolites and therapeutic drugs, and in transporter-mediated drug-drug ...Organic anion transporters (OATs) of the SLC22 family have crucial roles in the transport of organic anions, including metabolites and therapeutic drugs, and in transporter-mediated drug-drug interactions. In the kidneys, OATs facilitate the elimination of metabolic waste products and xenobiotics. However, their transport activities can lead to the accumulation of certain toxic compounds within cells, causing kidney damage. Moreover, OATs are important drug targets, because their inhibition modulates the elimination or retention of substrates linked to diseases. Despite extensive research on OATs, the molecular basis of their substrate and inhibitor binding remains poorly understood. Here we report the cryo-EM structures of rat OAT1 (also known as SLC22A6) and its complexes with para-aminohippuric acid and probenecid at 2.1, 2.8 and 2.9 Å resolution, respectively. Our findings reveal a highly conserved substrate binding mechanism for SLC22 transporters, wherein four aromatic residues form a cage to accommodate the polyspecific binding of diverse compounds. |
External links | Nat Struct Mol Biol / PubMed:37845412 |
Methods | EM (single particle) |
Resolution | 2.05 - 2.86 Å |
Structure data | EMDB-40352, PDB-8sdu: EMDB-40354, PDB-8sdy: EMDB-40355, PDB-8sdz: EMDB-40948: RELION reconstruction of rat organic anion transporter 1 (OAT1) |
Chemicals | ChemComp-HOH: ChemComp-ZWD: ChemComp-RTO: |
Source |
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Keywords | TRANSPORT PROTEIN / organic anion transporter / OAT / SLC22 / drug transporter / PAH / probenecid |