9klz
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Human OAT1 in complex with olmesartan== | |
| + | <StructureSection load='9klz' size='340' side='right'caption='[[9klz]], [[Resolution|resolution]] 3.88Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[9klz]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9KLZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9KLZ 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]] 3.88Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=OLM:OLMESARTAN'>OLM</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=9klz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9klz OCA], [https://pdbe.org/9klz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9klz RCSB], [https://www.ebi.ac.uk/pdbsum/9klz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9klz ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/S22A6_HUMAN S22A6_HUMAN] 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 2-oxoglutarate or glutarate (PubMed:11669456, PubMed:11907186, PubMed:14675047, PubMed:22108572, PubMed:23832370, PubMed:28534121, PubMed:9950961). 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 (PubMed:9887087). Functions 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 (PubMed:28534121). Transports prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) and may contribute to their renal excretion (PubMed:11907186). Also mediates the uptake of cyclic nucleotides such as cAMP and cGMP (PubMed:26377792). Involved in the transport of neuroactive tryptophan metabolites kynurenate (KYNA) and xanthurenate (XA) and may contribute to their secretion from the brain (PubMed:22108572, PubMed:23832370). May transport glutamate (PubMed:26377792). 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:11669456, PubMed:14675047). Uremic toxins include the indoxyl sulfate (IS), hippurate/N-benzoylglycine (HA), indole acetate (IA), 3-carboxy-4- methyl-5-propyl-2-furanpropionate (CMPF) and urate (PubMed:14675047, PubMed:26377792). Xenobiotics include the mycotoxin ochratoxin (OTA) (PubMed:11669456). May also contribute to the transport of organic compounds in testes across the blood-testis-barrier (PubMed:35307651).<ref>PMID:11669456</ref> <ref>PMID:11907186</ref> <ref>PMID:14675047</ref> <ref>PMID:22108572</ref> <ref>PMID:23832370</ref> <ref>PMID:26377792</ref> <ref>PMID:28534121</ref> <ref>PMID:35307651</ref> <ref>PMID:9887087</ref> <ref>PMID:9950961</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The organic anion transporter 1 (OAT1) plays a key role in excreting waste from organic drug metabolism and contributes significantly to drug-drug interactions and drug disposition. However, the structural basis of specific substrate and inhibitor transport by human OAT1 (hOAT1) has remained elusive. We determined four cryogenic electron microscopy (cryo-EM) structures of hOAT1 in its inward-facing conformation: the apo form, the substrate (olmesartan)-bound form with different anions, and the inhibitor (probenecid)-bound form. Structural and functional analyses revealed that Ser203 has an auxiliary role in chloride coordination, and it is a critical residue modulating olmesartan transport via chloride ion interactions. Structural comparisons indicate that inhibitors not only compete with substrates, but also obstruct substrate exit and entry from the cytoplasmic side, thereby increasing inhibitor retention. The findings can support drug development by providing insights into substrate recognition and the mechanism by which inhibitors arrest the OAT1 transport cycle. | ||
| - | + | Cryo-EM structures of human OAT1 reveal drug binding and inhibition mechanisms.,Jeon HM, Eun J, Kim KH, Kim Y Structure. 2025 Aug 14:S0969-2126(25)00267-9. doi: 10.1016/j.str.2025.07.019. PMID:40845848<ref>PMID:40845848</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 9klz" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Eun J]] | ||
| + | [[Category: Jeon HM]] | ||
| + | [[Category: Kim KH]] | ||
| + | [[Category: Kim Y]] | ||
Current revision
Human OAT1 in complex with olmesartan
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Categories: Homo sapiens | Large Structures | Eun J | Jeon HM | Kim KH | Kim Y
