View source for 8fhq


==Cryo-EM structure of human NCC (class 3-2)==
<StructureSection load='8fhq' size='340' side='right'caption='[[8fhq]], [[Resolution|resolution]] 2.81&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8fhq]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Danio_rerio Danio rerio] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8FHQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8FHQ 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]] 2.81&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=XZF:(3S)-6-chloro-2-methyl-1,1-dioxo-3-{[(2,2,2-trifluoroethyl)sulfanyl]methyl}-1,2,3,4-tetrahydro-1lambda~6~,2,4-benzothiadiazine-7-sulfonamide'>XZF</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=8fhq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8fhq OCA], [https://pdbe.org/8fhq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8fhq RCSB], [https://www.ebi.ac.uk/pdbsum/8fhq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8fhq ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/S12A3_HUMAN S12A3_HUMAN] Gitelman syndrome. The disease is caused by variants affecting the gene represented in this entry.
== Function ==
[https://www.uniprot.org/uniprot/S12A3_HUMAN S12A3_HUMAN] Electroneutral sodium and chloride ion cotransporter, which acts as a key mediator of sodium and chloride reabsorption in kidney distal convoluted tubules (PubMed:18270262, PubMed:21613606, PubMed:22009145, PubMed:36351028, PubMed:36792826). Also acts as a receptor for the pro-inflammatory cytokine IL18, thereby contributing to IL18-induced cytokine production, including IFNG, IL6, IL18 and CCL2 (By similarity). May act either independently of IL18R1, or in a complex with IL18R1 (By similarity).[UniProtKB:P59158]<ref>PMID:18270262</ref> <ref>PMID:21613606</ref> <ref>PMID:22009145</ref> <ref>PMID:36351028</ref> <ref>PMID:36792826</ref> [https://www.uniprot.org/uniprot/S12A2_DANRE S12A2_DANRE] Cation-chloride cotransporter which mediates the electroneutral transport of chloride, potassium and/or sodium ions across the membrane (PubMed:31367042). Plays a vital role in the regulation of ionic balance and cell volume (PubMed:31367042). Important for maintenance of endolymph volume in the otic vesicle, probably by regulating ion homeostasis (PubMed:19633174). Also plays a role in normal development of the swim bladder (PubMed:19633174).<ref>PMID:19633174</ref> <ref>PMID:31367042</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The sodium-chloride cotransporter (NCC) is critical for kidney physiology(1). The NCC has a major role in salt reabsorption in the distal convoluted tubule of the nephron(2,3), and mutations in the NCC cause the salt-wasting disease Gitelman syndrome(4). As a key player in salt handling, the NCC regulates blood pressure and is the target of thiazide diuretics, which have been widely prescribed as first-line medications to treat hypertension for more than 60 years(5-7). Here we determined the structures of human NCC alone and in complex with a commonly used thiazide diuretic using cryo-electron microscopy. These structures, together with functional studies, reveal major conformational states of the NCC and an intriguing regulatory mechanism. They also illuminate how thiazide diuretics specifically interact with the NCC and inhibit its transport function. Our results provide critical insights for understanding the Na-Cl cotransport mechanism of the NCC, and they establish a framework for future drug design and for interpreting disease-related mutations.

Structure and thiazide inhibition mechanism of the human Na-Cl cotransporter.,Fan M, Zhang J, Lee CL, Zhang J, Feng L Nature. 2023 Feb;614(7949):788-793. doi: 10.1038/s41586-023-05718-0. Epub 2023 , Feb 15. PMID:36792826<ref>PMID:36792826</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8fhq" style="background-color:#fffaf0;"></div>

==See Also==
*[[Solute carrier family 12 3D structures|Solute carrier family 12 3D structures]]
*[[Symporter 3D structures|Symporter 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Danio rerio]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Fan M]]
[[Category: Feng L]]
[[Category: Zhang J]]