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TitleThe substrate and inhibitor binding mechanism of polyspecific transporter OAT1 revealed by high-resolution cryo-EM.
Journal, issue, pagesNat Struct Mol Biol, Vol. 30, Issue 11, Page 1794-1805, Year 2023
Publish dateOct 16, 2023
AuthorsTongyi Dou / Tengfei Lian / Shi Shu / Yi He / Jiansen Jiang /
PubMed AbstractOrganic 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 linksNat Struct Mol Biol / PubMed:37845412
MethodsEM (single particle)
Resolution2.05 - 2.86 Å
Structure data

EMDB-40352, PDB-8sdu:
Structure of rat organic anion transporter 1 (OAT1)
Method: EM (single particle) / Resolution: 2.05 Å

EMDB-40354, PDB-8sdy:
Structure of rat organic anion transporter 1 (OAT1) in complex with para-aminohippuric acid (PAH)
Method: EM (single particle) / Resolution: 2.79 Å

EMDB-40355, PDB-8sdz:
Structure of rat organic anion transporter 1 (OAT1) in complex with probenecid
Method: EM (single particle) / Resolution: 2.86 Å

EMDB-40948: RELION reconstruction of rat organic anion transporter 1 (OAT1)
Method: EM (single particle) / Resolution: 2.23 Å

Chemicals

ChemComp-HOH:
WATER / Water

ChemComp-ZWD:
N-(4-aminobenzoyl)glycine

ChemComp-RTO:
4-(dipropylsulfamoyl)benzoic acid

Source
  • rattus norvegicus (Norway rat)
KeywordsTRANSPORT PROTEIN / organic anion transporter / OAT / SLC22 / drug transporter / PAH / probenecid

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