View source for 7xnl


==human KCNQ1-CaM-ML277-PIP2 complex in state A==
<StructureSection load='7xnl' size='340' side='right'caption='[[7xnl]], [[Resolution|resolution]] 3.10&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7xnl]] is a 8 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=7XNL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7XNL 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]] 3.1&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=I0S:(2R)-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-1-(4-methylbenzene-1-sulfonyl)piperidine-2-carboxamide'>I0S</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=PIO:[(2R)-2-OCTANOYLOXY-3-[OXIDANYL-[(1R,2R,3S,4R,5R,6S)-2,3,6-TRIS(OXIDANYL)-4,5-DIPHOSPHONOOXY-CYCLOHEXYL]OXY-PHOSPHORYL]OXY-PROPYL]+OCTANOATE'>PIO</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=7xnl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7xnl OCA], [https://pdbe.org/7xnl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7xnl RCSB], [https://www.ebi.ac.uk/pdbsum/7xnl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7xnl ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/KCNQ1_HUMAN KCNQ1_HUMAN] Defects in KCNQ1 are the cause of long QT syndrome type 1 (LQT1) [MIM:[https://omim.org/entry/192500 192500]; also known as Romano-Ward syndrome (RWS). Long QT syndromes are heart disorders characterized by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias. They cause syncope and sudden death in response to exercise or emotional stress. LQT1 inheritance is an autosomal dominant.<ref>PMID:18165683</ref> <ref>PMID:9799083</ref> <ref>PMID:10024302</ref> <ref>PMID:8528244</ref> <ref>PMID:9323054</ref> <ref>PMID:8872472</ref> <ref>PMID:8818942</ref> [:]<ref>PMID:9024139</ref> <ref>PMID:9386136</ref> <ref>PMID:9272155</ref> <ref>PMID:9302275</ref> <ref>PMID:9570196</ref> <ref>PMID:9641694</ref> <ref>PMID:9693036</ref> <ref>PMID:9482580</ref> <ref>PMID:9702906</ref> <ref>PMID:10367071</ref> <ref>PMID:9927399</ref> <ref>PMID:10482963</ref> <ref>PMID:10220144</ref> <ref>PMID:10220146</ref> <ref>PMID:10409658</ref> <ref>PMID:10728423</ref> <ref>PMID:10973849</ref> <ref>PMID:15840476</ref> <ref>PMID:19540844</ref> <ref>PMID:21241800</ref>   Defects in KCNQ1 are the cause of Jervell and Lange-Nielsen syndrome type 1 (JLNS1) [MIM:[https://omim.org/entry/220400 220400]. JLNS1 is an autosomal recessive disorder characterized by congenital deafness, prolongation of the QT interval, syncopal attacks due to ventricular arrhythmias, and a high risk of sudden death.<ref>PMID:10728423</ref> <ref>PMID:9781056</ref> <ref>PMID:10090886</ref>   Defects in KCNQ1 are the cause of familial atrial fibrillation type 3 (ATFB3) [MIM:[https://omim.org/entry/607554 607554]. Atrial fibrillation is a common disorder of cardiac rhythm that is hereditary in a small subgroup of patients. It is characterized by disorganized atrial electrical activity and ineffective atrial contraction promoting blood stasis in the atria and reduces ventricular filling. It can result in palpitations, syncope, thromboembolic stroke, and congestive heart failure.<ref>PMID:12522251</ref>   Defects in KCNQ1 are the cause of short QT syndrome type 2 (SQT2) [MIM:[https://omim.org/entry/609621 609621]. Short QT syndromes are heart disorders characterized by idiopathic persistently and uniformly short QT interval on ECG in the absence of structural heart disease in affected individuals. They cause syncope and sudden death.<ref>PMID:15159330</ref> 
== Function ==
[https://www.uniprot.org/uniprot/KCNQ1_HUMAN KCNQ1_HUMAN] Probably important in cardiac repolarization. Associates with KCNE1 (MinK) to form the I(Ks) cardiac potassium current. Elicits a rapidly activating, potassium-selective outward current. Muscarinic agonist oxotremorine-M strongly suppresses KCNQ1/KCNE1 current in CHO cells in which cloned KCNQ1/KCNE1 channels were coexpressed with M1 muscarinic receptors. May associate also with KCNE3 (MiRP2) to form the potassium channel that is important for cyclic AMP-stimulated intestinal secretion of chloride ions, which is reduced in cystic fibrosis and pathologically stimulated in cholera and other forms of secretory diarrhea.
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== Publication Abstract from PubMed ==
The cardiac KCNQ1 potassium channel carries the important I(Ks) current and controls the heart rhythm. Hundreds of mutations in KCNQ1 can cause life-threatening cardiac arrhythmia. Although KCNQ1 structures have been recently resolved, the structural basis for the dynamic electro-mechanical coupling, also known as the voltage sensor domain-pore domain (VSD-PD) coupling, remains largely unknown. In this study, utilizing two VSD-PD coupling enhancers, namely, the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP(2)) and a small-molecule ML277, we determined 2.5-3.5 A resolution cryo-electron microscopy structures of full-length human KCNQ1-calmodulin (CaM) complex in the apo closed, ML277-bound open, and ML277-PIP(2)-bound open states. ML277 binds at the "elbow" pocket above the S4-S5 linker and directly induces an upward movement of the S4-S5 linker and the opening of the activation gate without affecting the C-terminal domain (CTD) of KCNQ1. PIP(2) binds at the cleft between the VSD and the PD and brings a large structural rearrangement of the CTD together with the CaM to activate the PD. These findings not only elucidate the structural basis for the dynamic VSD-PD coupling process during KCNQ1 gating but also pave the way to develop new therapeutics for anti-arrhythmia.

Structural mechanisms for the activation of human cardiac KCNQ1 channel by electro-mechanical coupling enhancers.,Ma D, Zhong L, Yan Z, Yao J, Zhang Y, Ye F, Huang Y, Lai D, Yang W, Hou P, Guo J Proc Natl Acad Sci U S A. 2022 Nov 8;119(45):e2207067119. doi: , 10.1073/pnas.2207067119. Epub 2022 Nov 3. PMID:36763058<ref>PMID:36763058</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 7xnl" style="background-color:#fffaf0;"></div>

==See Also==
*[[Potassium channel 3D structures|Potassium channel 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Guo J]]
[[Category: Ma D]]