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1ih0

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Revision as of 10:38, 18 November 2020

Structure of the C-domain of Human Cardiac Troponin C in Complex with Ca2+ Sensitizer EMD 57033

Structural highlights

1ih0 is a 1 chain structure with sequence from Human. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	1aj4
Gene:	cTnC (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[TNNC1_HUMAN] Defects in TNNC1 are the cause of cardiomyopathy dilated type 1Z (CMD1Z) [MIM: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.^[1] Defects in TNNC1 are the cause of familial hypertrophic cardiomyopathy type 13 (CMH13) [MIM: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.^[2] ^[3] ^[4] ^[5]

Function

[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

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Ca(2+) binding to cardiac troponin C (cTnC) triggers contraction in heart muscle. In heart failure, myofilaments response to Ca(2+) are often altered and compounds that sensitize the myofilaments to Ca(2+) possess therapeutic value in this syndrome. One of the most potent and selective Ca(2+) sensitizers is the thiadiazinone derivative EMD 57033, which increases myocardial contractile function both in vivo and in vitro and interacts with cTnC in vitro. We have determined the NMR structure of the 1:1 complex between Ca(2+)-saturated C-domain of human cTnC (cCTnC) and EMD 57033. Favorable hydrophobic interactions between the drug and the protein position EMD 57033 in the hydrophobic cleft of the protein. The drug molecule is orientated such that the chiral group of EMD 57033 fits deep in the hydrophobic pocket and makes several key contacts with the protein. This stereospecific interaction explains why the (-)-enantiomer of EMD 57033 is inactive. Titrations of the cCTnC.EMD 57033 complex with two regions of cardiac troponin I (cTnI(34-71) and cTnI(128-147)) reveal that the drug does not share a common binding epitope with cTnI(128-147) but is completely displaced by cTnI(34-71). These results have important implications for elucidating the mechanism of the Ca(2+) sensitizing effect of EMD 57033 in cardiac muscle contraction.

Structure of the C-domain of human cardiac troponin C in complex with the Ca2+ sensitizing drug EMD 57033.,Wang X, Li MX, Spyracopoulos L, Beier N, Chandra M, Solaro RJ, Sykes BD J Biol Chem. 2001 Jul 6;276(27):25456-66. Epub 2001 Apr 24. PMID:11320096^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Mogensen J, Murphy RT, Shaw T, Bahl A, Redwood C, Watkins H, Burke M, Elliott PM, McKenna WJ. Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 2004 Nov 16;44(10):2033-40. PMID:15542288 doi:S0735-1097(04)01700-0
↑ Hoffmann B, Schmidt-Traub H, Perrot A, Osterziel KJ, Gessner R. First mutation in cardiac troponin C, L29Q, in a patient with hypertrophic cardiomyopathy. Hum Mutat. 2001 Jun;17(6):524. PMID:11385718 doi:10.1002/humu.1143
↑ Schmidtmann A, Lindow C, Villard S, Heuser A, Mugge A, Gessner R, Granier C, Jaquet K. Cardiac troponin C-L29Q, related to hypertrophic cardiomyopathy, hinders the transduction of the protein kinase A dependent phosphorylation signal from cardiac troponin I to C. FEBS J. 2005 Dec;272(23):6087-97. PMID:16302972 doi:10.1111/j.1742-4658.2005.05001.x
↑ Landstrom AP, Parvatiyar MS, Pinto JR, Marquardt ML, Bos JM, Tester DJ, Ommen SR, Potter JD, Ackerman MJ. Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C. J Mol Cell Cardiol. 2008 Aug;45(2):281-8. doi: 10.1016/j.yjmcc.2008.05.003. Epub , 2008 May 11. PMID:18572189 doi:10.1016/j.yjmcc.2008.05.003
↑ Pinto JR, Parvatiyar MS, Jones MA, Liang J, Ackerman MJ, Potter JD. A functional and structural study of troponin C mutations related to hypertrophic cardiomyopathy. J Biol Chem. 2009 Jul 10;284(28):19090-100. doi: 10.1074/jbc.M109.007021. Epub, 2009 May 12. PMID:19439414 doi:10.1074/jbc.M109.007021
↑ Wang X, Li MX, Spyracopoulos L, Beier N, Chandra M, Solaro RJ, Sykes BD. Structure of the C-domain of human cardiac troponin C in complex with the Ca2+ sensitizing drug EMD 57033. J Biol Chem. 2001 Jul 6;276(27):25456-66. Epub 2001 Apr 24. PMID:11320096 doi:10.1074/jbc.M102418200

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 See Also
7 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1ih0"

@@ Line 1: / Line 1: @@
 ==Structure of the C-domain of Human Cardiac Troponin C in Complex with Ca2+ Sensitizer EMD 57033==
-<StructureSection load='1ih0' size='340' side='right' caption='[[1ih0]], [[NMR_Ensembles_of_Models | 30 NMR models]]' scene=''>
+<StructureSection load='1ih0' size='340' side='right'caption='[[1ih0]], [[NMR_Ensembles_of_Models | 30 NMR models]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[1ih0]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1IH0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1IH0 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[1ih0]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1IH0 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=1IH0 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=EMD:5-[1-(3,4-DIMETHOXY-BENZOYL)-1,2,3,4-TETRAHYDRO-QUINOLIN-6-YL]-6-METHYL-3,6-DIHYDRO-[1,3,4]THIADIAZIN-2-ONE'>EMD</scene></td></tr>
+</td></tr><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=EMD:5-[1-(3,4-DIMETHOXY-BENZOYL)-1,2,3,4-TETRAHYDRO-QUINOLIN-6-YL]-6-METHYL-3,6-DIHYDRO-[1,3,4]THIADIAZIN-2-ONE'>EMD</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1aj4|1aj4]]</td></tr>
 <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">cTnC ([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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1ih0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ih0 OCA], [http://pdbe.org/1ih0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1ih0 RCSB], [http://www.ebi.ac.uk/pdbsum/1ih0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1ih0 ProSAT]</span></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=1ih0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ih0 OCA], [http://pdbe.org/1ih0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1ih0 RCSB], [http://www.ebi.ac.uk/pdbsum/1ih0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1ih0 ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 32: / Line 32: @@
 </div>
 <div class="pdbe-citations 1ih0" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Troponin|Troponin]]
 == References ==
 <references/>
@@ Line 37: / Line 40: @@
 </StructureSection>
 [[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Beier, N]]
 [[Category: Chandra, M]]

1ih0

From Proteopedia

Revision as of 10:38, 18 November 2020

Structure of the C-domain of Human Cardiac Troponin C in Complex with Ca2+ Sensitizer EMD 57033

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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