View source for 3u11


==Tetramerization dynamics of the C-terminus underlies isoform-specific cAMP-gating in HCN channels==
<StructureSection load='3u11' size='340' side='right'caption='[[3u11]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3u11]] is a 2 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=3U11 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3U11 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CMP:ADENOSINE-3,5-CYCLIC-MONOPHOSPHATE'>CMP</scene>, <scene name='pdbligand=CSO:S-HYDROXYCYSTEINE'>CSO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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=3u11 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3u11 OCA], [https://pdbe.org/3u11 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3u11 RCSB], [https://www.ebi.ac.uk/pdbsum/3u11 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3u11 ProSAT]</span></td></tr>
</table>
== 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 ==
[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;">
== Publication Abstract from PubMed ==
HCN channels are dually activated by hyperpolarization and binding of cAMP to their cyclic nucleotide binding domain (CNBD). HCN isoforms respond differently to cAMP: binding of cAMP shifts activation of HCN2 and HCN4 by 17 mV, but that of HCN1 by only 2-4 mV. To explain the peculiarity of HCN1 we solved the crystal structures and performed a biochemical-biophysical characterization of the C-terminal domain (C linker + CNBD) of the three isoforms. Our main finding is that tetramerization of the C-terminal domain of HCN1 occurs at basal cAMP concentrations while those of HCN2 and HCN4 require cAMP saturating levels. Therefore, HCN1 responds less markedly than HCN2 and HCN4 to cAMP increase because its CNBD is already partly tetrameric. This is confirmed by voltage clamp experiments showing that the right-shifted position of V1/2 in HCN1 is correlated with its propensity to tetramerize in vitro. These data underscore that ligand-induced CNBD tetramerization removes tonic inhibition from the pore of HCN channels.

Tetramerization dynamics of the C-terminal domain underlies isoform-specific cAMP-gating in Hyperpolarization-activated Cyclic Nucleotide gated channels.,Lolicato M, Nardini M, Gazzarrini S, Moeller S, Bertinetti D, Herberg FW, Bolognesi M, Martin H, Fasolini M, Bertrand JA, Arrigoni C, Thiel G, Moroni A J Biol Chem. 2011 Oct 17. PMID:22006928<ref>PMID:22006928</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 3u11" style="background-color:#fffaf0;"></div>

==See Also==
*[[Ion channels 3D structures|Ion channels 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Arrigoni C]]
[[Category: Bertinetti D]]
[[Category: Bertrand JA]]
[[Category: Bolognesi M]]
[[Category: Fasolini M]]
[[Category: Gazzarrini S]]
[[Category: Herberg FW]]
[[Category: Lolicato M]]
[[Category: Martin H]]
[[Category: Moller S]]
[[Category: Moroni A]]
[[Category: Nardini M]]
[[Category: Thiel G]]