View source for 8bvt


==Cryo-EM structure of rat SLC22A6 bound to probenecid==
<StructureSection load='8bvt' size='340' side='right'caption='[[8bvt]], [[Resolution|resolution]] 3.94&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8bvt]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_nativitatis Rattus nativitatis] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8BVT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8BVT FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.94&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=RTO:4-(dipropylsulfamoyl)benzoic+acid'>RTO</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8bvt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8bvt OCA], [https://pdbe.org/8bvt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8bvt RCSB], [https://www.ebi.ac.uk/pdbsum/8bvt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8bvt ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/S22A6_RAT S22A6_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]<ref>PMID:14675047</ref> <ref>PMID:23832370</ref> <ref>PMID:9228014</ref> <ref>PMID:9374486</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
In mammals, the kidney plays an essential role in maintaining blood homeostasis through the selective uptake, retention or elimination of toxins, drugs and metabolites. Organic anion transporters (OATs) are responsible for the recognition of metabolites and toxins in the nephron and their eventual urinary excretion. Inhibition of OATs is used therapeutically to improve drug efficacy and reduce nephrotoxicity. The founding member of the renal organic anion transporter family, OAT1 (also known as SLC22A6), uses the export of alpha-ketoglutarate (alpha-KG), a key intermediate in the Krebs cycle, to drive selective transport and is allosterically regulated by intracellular chloride. However, the mechanisms linking metabolite cycling, drug transport and intracellular chloride remain obscure. Here, we present cryogenic-electron microscopy structures of OAT1 bound to alpha-KG, the antiviral tenofovir and clinical inhibitor probenecid, used in the treatment of Gout. Complementary in vivo cellular assays explain the molecular basis for alpha-KG driven drug elimination and the allosteric regulation of organic anion transport in the kidney by chloride.

Molecular basis for selective uptake and elimination of organic anions in the kidney by OAT1.,Parker JL, Kato T, Kuteyi G, Sitsel O, Newstead S Nat Struct Mol Biol. 2023 Nov;30(11):1786-1793. doi: 10.1038/s41594-023-01039-y. , Epub 2023 Jul 23. PMID:37482561<ref>PMID:37482561</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8bvt" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Rattus nativitatis]]
[[Category: Synthetic construct]]
[[Category: Kato T]]
[[Category: Newstead S]]
[[Category: Parker JL]]