8sdu
Structure of rat organic anion transporter 1 (OAT1)
Structural highlights
FunctionS22A6_RAT Secondary active transporter that functions as a Na(+)-independent organic anion (OA)/dicarboxylate antiporter where the uptake of one molecule of OA into the cell is coupled with an efflux of one molecule of intracellular dicarboxylate such as alpha-ketoglutarate or glutarate (PubMed:14675047, PubMed:23832370, PubMed:9228014, PubMed:9374486). Mediates the uptake of OA across the basolateral side of proximal tubule epithelial cells, thereby contributing to the renal elimination of endogenous OA from the systemic circulation into the urine (By similarity). Function as a biopterin transporters involved in the uptake and the secretion of coenzymes tetrahydrobiopterin (BH4) dihydrobiopterin (BH2) and sepiapterin to urine, thereby determining baseline levels of blood biopterins (By similarity). Transports prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) and may contribute to their renal excretion (PubMed:9228014). Also mediates the uptake of cyclic nucleotides such as cAMP and cGMP (PubMed:9228014). Involved in the transport of neuroactive tryptophan metabolites kynurenate (KYNA) and xanthurenate (XA) and may contribute to their secretion from the brain (PubMed:23832370). May transport glutamate (By similarity). Also involved in the disposition of uremic toxins and potentially toxic xenobiotics by the renal organic anion secretory pathway, helping reduce their undesired toxicological effects on the body (PubMed:14675047, PubMed:9228014). Uremic toxins include the indoxyl sulfate (IS), hippurate, indole acetate (IA), 3-carboxy-4- methyl-5-propyl-2-furanpropionate(CMPF) and urate (PubMed:14675047, PubMed:9228014). Xenobiotics include the mycotoxin ochratoxin (OTA) (By similarity). May also contribute to the transport of organic compounds in testes across the blood-testis-barrier (By similarity). May also work as a bidirectional OA/dicarboxylate exchanger (PubMed:9228014).[UniProtKB:Q4U2R8][1] [2] [3] [4] Publication Abstract from PubMedOrganic 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 A 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. The substrate and inhibitor binding mechanism of polyspecific transporter OAT1 revealed by high-resolution cryo-EM.,Dou T, Lian T, Shu S, He Y, Jiang J Nat Struct Mol Biol. 2023 Nov;30(11):1794-1805. doi: 10.1038/s41594-023-01123-3. , Epub 2023 Oct 16. PMID:37845412[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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