View source for 6rv3


==Crystal structure of the human two pore domain potassium ion channel TASK-1 (K2P3.1) in a closed conformation with a bound inhibitor BAY 1000493==
<StructureSection load='6rv3' size='340' side='right'caption='[[6rv3]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6rv3]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6RV3 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6RV3 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMU:DECYL-BETA-D-MALTOPYRANOSIDE'>DMU</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=KKQ:[4-[[2-(4-bromophenyl)imidazo[1,2-a]pyridin-3-yl]methyl]piperazin-1-yl]-(2-fluorophenyl)methanone'>KKQ</scene>, <scene name='pdbligand=PC1:1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE'>PC1</scene>, <scene name='pdbligand=Y01:CHOLESTEROL+HEMISUCCINATE'>Y01</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">KCNK3, TASK, TASK1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6rv3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6rv3 OCA], [http://pdbe.org/6rv3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6rv3 RCSB], [http://www.ebi.ac.uk/pdbsum/6rv3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6rv3 ProSAT]</span></td></tr>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/KCNK3_HUMAN KCNK3_HUMAN]] Heritable pulmonary arterial hypertension. The disease is caused by mutations affecting the gene represented in this entry. 
== Function ==
[[http://www.uniprot.org/uniprot/KCNK3_HUMAN KCNK3_HUMAN]] pH-dependent, voltage-insensitive, background potassium channel protein. Rectification direction results from potassium ion concentration on either side of the membrane. Acts as an outward rectifier when external potassium concentration is low. When external potassium concentration is high, current is inward.<ref>PMID:23169818</ref> <ref>PMID:9312005</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
TWIK-related acid-sensitive potassium (TASK) channels-members of the two pore domain potassium (K2P) channel family-are found in neurons(1), cardiomyocytes(2-4) and vascular smooth muscle cells(5), where they are involved in the regulation of heart rate(6), pulmonary artery tone(5,7), sleep/wake cycles(8) and responses to volatile anaesthetics(8-11). K2P channels regulate the resting membrane potential, providing background K(+) currents controlled by numerous physiological stimuli(12-15). Unlike other K2P channels, TASK channels are able to bind inhibitors with high affinity, exceptional selectivity and very slow compound washout rates. As such, these channels are attractive drug targets, and TASK-1 inhibitors are currently in clinical trials for obstructive sleep apnoea and atrial fibrillation(16). In general, potassium channels have an intramembrane vestibule with a selectivity filter situated above and a gate with four parallel helices located below; however, the K2P channels studied so far all lack a lower gate. Here we present the X-ray crystal structure of TASK-1, and show that it contains a lower gate-which we designate as an 'X-gate'-created by interaction of the two crossed C-terminal M4 transmembrane helices at the vestibule entrance. This structure is formed by six residues ((243)VLRFMT(248)) that are essential for responses to volatile anaesthetics(10), neurotransmitters(13) and G-protein-coupled receptors(13). Mutations within the X-gate and the surrounding regions markedly affect both the channel-open probability and the activation of the channel by anaesthetics. Structures of TASK-1 bound to two high-affinity inhibitors show that both compounds bind below the selectivity filter and are trapped in the vestibule by the X-gate, which explains their exceptionally low washout rates. The presence of the X-gate in TASK channels explains many aspects of their physiological and pharmacological behaviour, which will be beneficial for the future development and optimization of TASK modulators for the treatment of heart, lung and sleep disorders.

A lower X-gate in TASK channels traps inhibitors within the vestibule.,Rodstrom KEJ, Kiper AK, Zhang W, Rinne S, Pike ACW, Goldstein M, Conrad LJ, Delbeck M, Hahn MG, Meier H, Platzk M, Quigley A, Speedman D, Shrestha L, Mukhopadhyay SMM, Burgess-Brown NA, Tucker SJ, Muller T, Decher N, Carpenter EP Nature. 2020 Jun;582(7812):443-447. doi: 10.1038/s41586-020-2250-8. Epub 2020 Apr, 29. PMID:32499642<ref>PMID:32499642</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6rv3" style="background-color:#fffaf0;"></div>

==See Also==
*[[Potassium channel 3D structures|Potassium channel 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Arrowsmith, C H]]
[[Category: Bountra, C]]
[[Category: Burgess-Brown, N]]
[[Category: Bushell, S R]]
[[Category: Carpenter, E P]]
[[Category: Chalk, R]]
[[Category: Edwards, A M]]
[[Category: Mukhopadhyay, S M.M]]
[[Category: Pike, A C.W]]
[[Category: Quigley, A]]
[[Category: Rodstrom, K E.J]]
[[Category: Structural genomic]]
[[Category: Shrestha, L]]
[[Category: Speedman, D]]
[[Category: Tessitore, A]]
[[Category: Venkaya, S]]
[[Category: Zhang, W]]
[[Category: Membrane protein]]
[[Category: Potassium channel]]
[[Category: Sgc]]