4kl1: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
==HCN4 CNBD in complex with cGMP== | ==HCN4 CNBD in complex with cGMP== | ||
<StructureSection load='4kl1' size='340' side='right' caption='[[4kl1]], [[Resolution|resolution]] 2.70Å' scene=''> | <StructureSection load='4kl1' size='340' side='right'caption='[[4kl1]], [[Resolution|resolution]] 2.70Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4kl1]] is a 4 chain structure with sequence from [ | <table><tr><td colspan='2'>[[4kl1]] is a 4 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=4KL1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4KL1 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand= | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CSO:S-HYDROXYCYSTEINE'>CSO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PCG:CYCLIC+GUANOSINE+MONOPHOSPHATE'>PCG</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=4kl1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4kl1 OCA], [https://pdbe.org/4kl1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4kl1 RCSB], [https://www.ebi.ac.uk/pdbsum/4kl1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4kl1 ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Disease == | == Disease == | ||
[ | [https://www.uniprot.org/uniprot/HCN4_HUMAN HCN4_HUMAN] Sick sinus syndrome;Brugada syndrome. Sick sinus syndrome 2 (SSS2) [MIM:[https://omim.org/entry/163800 163800]: The term 'sick sinus syndrome' encompasses a variety of conditions caused by sinus node dysfunction. The most common clinical manifestations are syncope, presyncope, dizziness, and fatigue. Electrocardiogram typically shows sinus bradycardia, sinus arrest, and/or sinoatrial block. Episodes of atrial tachycardias coexisting with sinus bradycardia ('tachycardia-bradycardia syndrome') are also common in this disorder. SSS occurs most often in the elderly associated with underlying heart disease or previous cardiac surgery, but can also occur in the fetus, infant, or child without heart disease or other contributing factors. SSS2 onset is in utero or at birth. Note=The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:16407510</ref> <ref>PMID:20662977</ref> Brugada syndrome 8 (BRGDA8) [MIM:[https://omim.org/entry/613123 613123]: A tachyarrhythmia characterized by right bundle branch block and ST segment elevation on an electrocardiogram (ECG). It can cause the ventricles to beat so fast that the blood is prevented from circulating efficiently in the body. When this situation occurs, the individual will faint and may die in a few minutes if the heart is not reset. Note=The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:19165230</ref> | ||
== Function == | == Function == | ||
[ | [https://www.uniprot.org/uniprot/HCN4_HUMAN HCN4_HUMAN] Hyperpolarization-activated ion channel with very slow activation and inactivation exhibiting weak selectivity for potassium over sodium ions. May contribute to the native pacemaker currents in heart (If) and in neurons (Ih). Activated by cAMP. May mediate responses to sour stimuli.<ref>PMID:10228147</ref> <ref>PMID:10430953</ref> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 25: | Line 22: | ||
==See Also== | ==See Also== | ||
*[[Ion channels|Ion channels]] | *[[Ion channels 3D structures|Ion channels 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: Arrigoni | [[Category: Large Structures]] | ||
[[Category: Bolognesi | [[Category: Arrigoni C]] | ||
[[Category: Bucchi | [[Category: Bolognesi M]] | ||
[[Category: DiFrancesco | [[Category: Bucchi A]] | ||
[[Category: Fishwick | [[Category: DiFrancesco D]] | ||
[[Category: Johnson | [[Category: Fishwick CWG]] | ||
[[Category: Lolicato | [[Category: Johnson APK]] | ||
[[Category: Moroni | [[Category: Lolicato M]] | ||
[[Category: Nardini | [[Category: Moroni A]] | ||
[[Category: Schroeder | [[Category: Nardini M]] | ||
[[Category: Schwede | [[Category: Schroeder I]] | ||
[[Category: Simmons | [[Category: Schwede F]] | ||
[[Category: Thiel | [[Category: Simmons K]] | ||
[[Category: Zucca | [[Category: Thiel G]] | ||
[[Category: Zucca S]] | |||
Revision as of 11:57, 7 December 2022
HCN4 CNBD in complex with cGMPHCN4 CNBD in complex with cGMP
Structural highlights
DiseaseHCN4_HUMAN Sick sinus syndrome;Brugada syndrome. Sick sinus syndrome 2 (SSS2) [MIM:163800: The term 'sick sinus syndrome' encompasses a variety of conditions caused by sinus node dysfunction. The most common clinical manifestations are syncope, presyncope, dizziness, and fatigue. Electrocardiogram typically shows sinus bradycardia, sinus arrest, and/or sinoatrial block. Episodes of atrial tachycardias coexisting with sinus bradycardia ('tachycardia-bradycardia syndrome') are also common in this disorder. SSS occurs most often in the elderly associated with underlying heart disease or previous cardiac surgery, but can also occur in the fetus, infant, or child without heart disease or other contributing factors. SSS2 onset is in utero or at birth. Note=The disease is caused by mutations affecting the gene represented in this entry.[1] [2] Brugada syndrome 8 (BRGDA8) [MIM:613123: A tachyarrhythmia characterized by right bundle branch block and ST segment elevation on an electrocardiogram (ECG). It can cause the ventricles to beat so fast that the blood is prevented from circulating efficiently in the body. When this situation occurs, the individual will faint and may die in a few minutes if the heart is not reset. Note=The disease is caused by mutations affecting the gene represented in this entry.[3] FunctionHCN4_HUMAN Hyperpolarization-activated ion channel with very slow activation and inactivation exhibiting weak selectivity for potassium over sodium ions. May contribute to the native pacemaker currents in heart (If) and in neurons (Ih). Activated by cAMP. May mediate responses to sour stimuli.[4] [5] Publication Abstract from PubMedcAMP mediates autonomic regulation of heart rate by means of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which underlie the pacemaker current If. cAMP binding to the C-terminal cyclic nucleotide binding domain enhances HCN open probability through a conformational change that reaches the pore via the C-linker. Using structural and functional analysis, we identified a binding pocket in the C-linker of HCN4. Cyclic dinucleotides, an emerging class of second messengers in mammals, bind the C-linker pocket (CLP) and antagonize cAMP regulation of the channel. Accordingly, cyclic dinucleotides prevent cAMP regulation of If in sinoatrial node myocytes, reducing heart rate by 30%. Occupancy of the CLP hence constitutes an efficient mechanism to hinder beta-adrenergic stimulation on If. Our results highlight the regulative role of the C-linker and identify a potential drug target in HCN4. Furthermore, these data extend the signaling scope of cyclic dinucleotides in mammals beyond their first reported role in innate immune system. Cyclic dinucleotides bind the C-linker of HCN4 to control channel cAMP responsiveness.,Lolicato M, Bucchi A, Arrigoni C, Zucca S, Nardini M, Schroeder I, Simmons K, Aquila M, DiFrancesco D, Bolognesi M, Schwede F, Kashin D, Fishwick CW, Johnson AP, Thiel G, Moroni A Nat Chem Biol. 2014 Jun;10(6):457-62. doi: 10.1038/nchembio.1521. Epub 2014 Apr, 28. PMID:24776929[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||