2l1r
From Proteopedia
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==The structure of the calcium-sensitizer, dfbp-o, in complex with the N-domain of troponin C and the switch region of troponin I== | ==The structure of the calcium-sensitizer, dfbp-o, in complex with the N-domain of troponin C and the switch region of troponin I== | ||
| - | <StructureSection load='2l1r' size='340' side='right'caption='[[2l1r | + | <StructureSection load='2l1r' size='340' side='right'caption='[[2l1r]]' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[2l1r]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/ | + | <table><tr><td colspan='2'>[[2l1r]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2L1R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2L1R FirstGlance]. <br> |
| - | </td></tr><tr id=' | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</td></tr> |
| - | <tr id=' | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=SXK:[(2,4-DIFLUOROBIPHENYL-4-YL)OXY]ACETIC+ACID'>SXK</scene></td></tr> |
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2l1r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2l1r OCA], [https://pdbe.org/2l1r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2l1r RCSB], [https://www.ebi.ac.uk/pdbsum/2l1r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2l1r ProSAT]</span></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=2l1r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2l1r OCA], [https://pdbe.org/2l1r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2l1r RCSB], [https://www.ebi.ac.uk/pdbsum/2l1r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2l1r ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Disease == | == Disease == | ||
| - | + | [https://www.uniprot.org/uniprot/TNNC1_HUMAN TNNC1_HUMAN] Defects in TNNC1 are the cause of cardiomyopathy dilated type 1Z (CMD1Z) [MIM:[https://omim.org/entry/611879 611879]. Dilated cardiomyopathy is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.<ref>PMID:15542288</ref> Defects in TNNC1 are the cause of familial hypertrophic cardiomyopathy type 13 (CMH13) [MIM:[https://omim.org/entry/613243 613243]. A hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death.<ref>PMID:11385718</ref> <ref>PMID:16302972</ref> <ref>PMID:18572189</ref> <ref>PMID:19439414</ref> | |
== Function == | == Function == | ||
| - | + | [https://www.uniprot.org/uniprot/TNNC1_HUMAN TNNC1_HUMAN] Troponin is the central regulatory protein of striated muscle contraction. Tn consists of three components: Tn-I which is the inhibitor of actomyosin ATPase, Tn-T which contains the binding site for tropomyosin and Tn-C. The binding of calcium to Tn-C abolishes the inhibitory action of Tn on actin filaments. | |
== Evolutionary Conservation == | == Evolutionary Conservation == | ||
[[Image:Consurf_key_small.gif|200px|right]] | [[Image:Consurf_key_small.gif|200px|right]] | ||
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2l1r ConSurf]. | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2l1r ConSurf]. | ||
<div style="clear:both"></div> | <div style="clear:both"></div> | ||
| - | <div style="background-color:#fffaf0;"> | ||
| - | == Publication Abstract from PubMed == | ||
| - | The Ca(2+) dependant interaction between troponin I (cTnI) and troponin C (cTnC) triggers contraction in heart muscle. Heart failure is characterized by a decrease in cardiac output, and compounds that increase the sensitivity of cardiac muscle to Ca(2+) have therapeutic potential. The Ca(2+)-sensitizer, levosimendan, targets cTnC; however, detailed understanding of its mechanism has been obscured by its instability. In order to understand how this class of positive inotropes function, we investigated the mode of action of two fluorine containing novel analogs of levosimendan; 2',4'-difluoro(1,1'-biphenyl)-4-yloxy acetic acid (dfbp-o) and 2',4'-difluoro(1,1'-biphenyl)-4-yl acetic acid (dfbp). The affinities of dfbp and dfbp-o for the regulatory domain of cTnC were measured in the absence and presence of cTnI by NMR spectroscopy, and dfbp-o was found to bind more strongly than dfbp. Dfbp-o also increased the affinity of cTnI for cTnC. Dfbp-o increased the Ca(2+)-sensitivity of demembranated cardiac trabeculae in a manner similar to levosimendan. The high resolution NMR solution structure of the cTnC-cTnI-dfbp-o ternary complex showed that dfbp-o bound at the hydrophobic interface formed by cTnC and cTnI making critical interactions with residues such as Arg147 of cTnI. In the absence of cTnI, docking localized dfbp-o to the same position in the hydrophobic groove of cTnC. The structural and functional data reveal that the levosimendan class of Ca(2+/-)-sensitizers work by binding to the regulatory domain of cTnC and stabilizing the pivotal cTnC-cTnI regulatory unit via a network of hydrophobic and electrostatic interactions, in contrast to the destabilizing effects of antagonists such as W7 at the same interface. | ||
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| - | A structural and functional perspective into the mechanism of Ca(2+)-sensitizers that target the cardiac troponin complex.,Robertson IM, Sun YB, Li MX, Sykes BD J Mol Cell Cardiol. 2010 Aug 27. PMID:20801130<ref>PMID:20801130</ref> | ||
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| - | </div> | ||
| - | <div class="pdbe-citations 2l1r" style="background-color:#fffaf0;"></div> | ||
==See Also== | ==See Also== | ||
| - | *[[Troponin|Troponin]] | + | *[[Troponin 3D structures|Troponin 3D structures]] |
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| - | [[Category: | + | [[Category: Homo sapiens]] |
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Li | + | [[Category: Li MX]] |
| - | [[Category: Robertson | + | [[Category: Robertson IM]] |
| - | [[Category: Sun | + | [[Category: Sun Y]] |
| - | [[Category: Sykes | + | [[Category: Sykes BD]] |
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Current revision
The structure of the calcium-sensitizer, dfbp-o, in complex with the N-domain of troponin C and the switch region of troponin I
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Categories: Homo sapiens | Large Structures | Li MX | Robertson IM | Sun Y | Sykes BD
