9b1l
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | The entry | + | ==Urate bound human URAT1 in the outward-facing state.== |
| + | <StructureSection load='9b1l' size='340' side='right'caption='[[9b1l]], [[Resolution|resolution]] 3.10Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[9b1l]] 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=9B1L OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9B1L 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]] 3.1Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=URC:URIC+ACID'>URC</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=9b1l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9b1l OCA], [https://pdbe.org/9b1l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9b1l RCSB], [https://www.ebi.ac.uk/pdbsum/9b1l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9b1l ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [https://www.uniprot.org/uniprot/S22AC_HUMAN S22AC_HUMAN] Hereditary renal hypouricemia. The disease is caused by variants affecting the gene represented in this entry. | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/S22AC_HUMAN S22AC_HUMAN] Electroneutral antiporter that translocates urate across the apical membrane of proximal tubular cells in exchange for monovalent organic or inorganic anions (PubMed:12024214, PubMed:22194875, PubMed:35144162, PubMed:35462902). Involved in renal reabsorption of urate and helps maintaining blood levels of uric acid (PubMed:12024214, PubMed:22194875). Mediates urate uptake by an exchange with organic anions such as (S)-lactate and nicotinate, and inorganic anion Cl(-) (PubMed:12024214). Other inorganic anions such as Br(-), I(-) and NO3(-) may also act as counteranions that exchange for urate (PubMed:12024214). Also mediates orotate tubular uptake coupled with nicotinate efflux and to a lesser extent with lactate efflux, therefore displaying a potential role in orotate renal reabsorption (PubMed:21350910). Orotate transport is Cl(-)-dependent (PubMed:21350910).<ref>PMID:12024214</ref> <ref>PMID:21350910</ref> <ref>PMID:22194875</ref> <ref>PMID:35144162</ref> <ref>PMID:35462902</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Urate is an endogenous product of purine metabolism in the liver. High urate levels in the blood lead to gout, a very common and painful inflammatory arthritis. Excreted urate is reabsorbed in the kidney mainly by URAT1 antiporter, a key target for anti-gout drugs. To uncover the mechanisms of urate transport and drug inhibition, we determined cryo-EM structures of human URAT1 with urate, counter anion pyrazinoate, or anti-gout drugs of different chemotypes - lesinurad, verinurad, and dotinurad. We captured the outward-to-inward transition of URAT1 during urate uptake, revealing that urate binds in a phenylalanine-rich pocket and engages with key gating residues to drive the transport cycle. In contrast to the single binding site for urate, pyrazinoate interacts with three distinct, functionally relevant sites within URAT1, a mechanism that has not yet been observed in other anion antiporters. In addition, we found that while all three drugs compete with substrates and halt the transport cycle, verinurad and dotinurad further hijack gating residues to achieve high potency. These insights advance our understanding of organic anion transport and provide a foundation for designing improved gout therapeutics. | ||
| - | + | Transport mechanism and structural pharmacology of human urate transporter URAT1.,Dai Y, Lee CH Cell Res. 2024 Sep 9. doi: 10.1038/s41422-024-01023-1. PMID:39245778<ref>PMID:39245778</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 9b1l" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Dai Y]] | ||
| + | [[Category: Lee CH]] | ||
Current revision
Urate bound human URAT1 in the outward-facing state.
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