|
|
| (18 intermediate revisions not shown.) |
| Line 1: |
Line 1: |
| - | [[Image:1lxf.gif|left|200px]]<br /> | |
| - | <applet load="1lxf" size="450" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="1lxf" /> | |
| - | '''Structure of the Regulatory N-domain of Human Cardiac Troponin C in Complex with Human Cardiac Troponin-I(147-163) and Bepridil'''<br /> | |
| | | | |
| - | ==Overview== | + | ==Structure of the Regulatory N-domain of Human Cardiac Troponin C in Complex with Human Cardiac Troponin-I(147-163) and Bepridil== |
| - | Cardiac troponin C (cTnC) is the Ca(2+)-dependent switch for contraction, in heart muscle and a potential target for drugs in the therapy of heart, failure. Ca(2+) binding to the regulatory domain of cTnC (cNTnC) induces, little structural change but sets the stage for cTnI binding. A large, "closed" to "open" conformational transition occurs in the regulatory, domain upon binding cTnI(147-163) or bepridil. This raises the question of, whether cTnI(147-163) and bepridil compete for cNTnC.Ca(2+). In this work, we used two-dimensional (1)H,(15)N-heteronuclear single quantum coherence, (HSQC) NMR spectroscopy to examine the binding of bepridil to cNTnC.Ca(2+), in the absence and presence of cTnI(147-163) and of cTnI(147-163) to, cNTnC.Ca(2+) in the absence and presence of bepridil. The results show, that bepridil and cTnI(147-163) bind cNTnC.Ca(2+) simultaneously but with, negative cooperativity. The affinity of cTnI(147-163) for cNTnC.Ca(2+) is, reduced approximately 3.5-fold by bepridil and vice versa. Using, multinuclear and multidimensional NMR spectroscopy, we have determined the, structure of the cNTnC.Ca(2+).cTnI(147-163).bepridil ternary complex. The, structure reveals a binding site for cTnI(147-163) primarily located on, the A/B interhelical interface and a binding site for bepridil in the, hydrophobic pocket of cNTnC.Ca(2+). In the structure, the N terminus of, the peptide clashes with part of the bepridil molecule, which explains the, negative cooperativity between cTnI(147-163) and bepridil for, cNTnC.Ca(2+). This structure provides insights into the features that are, important for the design of cTnC-specific cardiotonic drugs, which may be, used to modulate the Ca(2+) sensitivity of the myofilaments in heart, muscle contraction. | + | <StructureSection load='1lxf' size='340' side='right'caption='[[1lxf]]' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[1lxf]] 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=1LXF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1LXF FirstGlance]. <br> |
| | + | </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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BEP:1-ISOBUTOXY-2-PYRROLIDINO-3[N-BENZYLANILINO]+PROPANE'>BEP</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</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=1lxf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1lxf OCA], [https://pdbe.org/1lxf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1lxf RCSB], [https://www.ebi.ac.uk/pdbsum/1lxf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1lxf ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == 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 == |
| | + | [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 == |
| | + | [[Image:Consurf_key_small.gif|200px|right]] |
| | + | Check<jmol> |
| | + | <jmolCheckbox> |
| | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/lx/1lxf_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | + | <text>to colour the structure by Evolutionary Conservation</text> |
| | + | </jmolCheckbox> |
| | + | </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=1lxf ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | Cardiac troponin C (cTnC) is the Ca(2+)-dependent switch for contraction in heart muscle and a potential target for drugs in the therapy of heart failure. Ca(2+) binding to the regulatory domain of cTnC (cNTnC) induces little structural change but sets the stage for cTnI binding. A large "closed" to "open" conformational transition occurs in the regulatory domain upon binding cTnI(147-163) or bepridil. This raises the question of whether cTnI(147-163) and bepridil compete for cNTnC.Ca(2+). In this work, we used two-dimensional (1)H,(15)N-heteronuclear single quantum coherence (HSQC) NMR spectroscopy to examine the binding of bepridil to cNTnC.Ca(2+) in the absence and presence of cTnI(147-163) and of cTnI(147-163) to cNTnC.Ca(2+) in the absence and presence of bepridil. The results show that bepridil and cTnI(147-163) bind cNTnC.Ca(2+) simultaneously but with negative cooperativity. The affinity of cTnI(147-163) for cNTnC.Ca(2+) is reduced approximately 3.5-fold by bepridil and vice versa. Using multinuclear and multidimensional NMR spectroscopy, we have determined the structure of the cNTnC.Ca(2+).cTnI(147-163).bepridil ternary complex. The structure reveals a binding site for cTnI(147-163) primarily located on the A/B interhelical interface and a binding site for bepridil in the hydrophobic pocket of cNTnC.Ca(2+). In the structure, the N terminus of the peptide clashes with part of the bepridil molecule, which explains the negative cooperativity between cTnI(147-163) and bepridil for cNTnC.Ca(2+). This structure provides insights into the features that are important for the design of cTnC-specific cardiotonic drugs, which may be used to modulate the Ca(2+) sensitivity of the myofilaments in heart muscle contraction. |
| | | | |
| - | ==Disease==
| + | Structure of the regulatory N-domain of human cardiac troponin C in complex with human cardiac troponin I147-163 and bepridil.,Wang X, Li MX, Sykes BD J Biol Chem. 2002 Aug 23;277(34):31124-33. Epub 2002 Jun 11. PMID:12060657<ref>PMID:12060657</ref> |
| - | Known diseases associated with this structure: Cardiomyopathy, familial hypertrophic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191044 191044]], Cardiomyopathy, familial hypertrophic, 192600 (3) OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191040 191040]], Cardiomyopathy, familial restrictive OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191044 191044]]
| + | |
| | | | |
| - | ==About this Structure==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | 1LXF is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with CA and BEP as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1LXF OCA].
| + | </div> |
| | + | <div class="pdbe-citations 1lxf" style="background-color:#fffaf0;"></div> |
| | | | |
| - | ==Reference== | + | ==See Also== |
| - | Structure of the regulatory N-domain of human cardiac troponin C in complex with human cardiac troponin I147-163 and bepridil., Wang X, Li MX, Sykes BD, J Biol Chem. 2002 Aug 23;277(34):31124-33. Epub 2002 Jun 11. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=12060657 12060657]
| + | *[[Troponin 3D structures|Troponin 3D structures]] |
| | + | == References == |
| | + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Protein complex]] | + | [[Category: Large Structures]] |
| - | [[Category: Li, M.X.]] | + | [[Category: Li MX]] |
| - | [[Category: Sykes, B.D.]] | + | [[Category: Sykes BD]] |
| - | [[Category: Wang, X.]] | + | [[Category: Wang X]] |
| - | [[Category: BEP]]
| + | |
| - | [[Category: CA]]
| + | |
| - | [[Category: bepridil]]
| + | |
| - | [[Category: cardiac troponin c-drug interaction]]
| + | |
| - | [[Category: cardiac troponin i-drug interaction]]
| + | |
| - | [[Category: muscle]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 18:04:54 2007''
| + | |
| Structural highlights
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
Cardiac troponin C (cTnC) is the Ca(2+)-dependent switch for contraction in heart muscle and a potential target for drugs in the therapy of heart failure. Ca(2+) binding to the regulatory domain of cTnC (cNTnC) induces little structural change but sets the stage for cTnI binding. A large "closed" to "open" conformational transition occurs in the regulatory domain upon binding cTnI(147-163) or bepridil. This raises the question of whether cTnI(147-163) and bepridil compete for cNTnC.Ca(2+). In this work, we used two-dimensional (1)H,(15)N-heteronuclear single quantum coherence (HSQC) NMR spectroscopy to examine the binding of bepridil to cNTnC.Ca(2+) in the absence and presence of cTnI(147-163) and of cTnI(147-163) to cNTnC.Ca(2+) in the absence and presence of bepridil. The results show that bepridil and cTnI(147-163) bind cNTnC.Ca(2+) simultaneously but with negative cooperativity. The affinity of cTnI(147-163) for cNTnC.Ca(2+) is reduced approximately 3.5-fold by bepridil and vice versa. Using multinuclear and multidimensional NMR spectroscopy, we have determined the structure of the cNTnC.Ca(2+).cTnI(147-163).bepridil ternary complex. The structure reveals a binding site for cTnI(147-163) primarily located on the A/B interhelical interface and a binding site for bepridil in the hydrophobic pocket of cNTnC.Ca(2+). In the structure, the N terminus of the peptide clashes with part of the bepridil molecule, which explains the negative cooperativity between cTnI(147-163) and bepridil for cNTnC.Ca(2+). This structure provides insights into the features that are important for the design of cTnC-specific cardiotonic drugs, which may be used to modulate the Ca(2+) sensitivity of the myofilaments in heart muscle contraction.
Structure of the regulatory N-domain of human cardiac troponin C in complex with human cardiac troponin I147-163 and bepridil.,Wang X, Li MX, Sykes BD J Biol Chem. 2002 Aug 23;277(34):31124-33. Epub 2002 Jun 11. PMID:12060657[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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, Sykes BD. Structure of the regulatory N-domain of human cardiac troponin C in complex with human cardiac troponin I147-163 and bepridil. J Biol Chem. 2002 Aug 23;277(34):31124-33. Epub 2002 Jun 11. PMID:12060657 doi:10.1074/jbc.M203896200
|
