1ih0
From Proteopedia
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|PDB= 1ih0 |SIZE=350|CAPTION= <scene name='initialview01'>1ih0</scene> | |PDB= 1ih0 |SIZE=350|CAPTION= <scene name='initialview01'>1ih0</scene> | ||
|SITE= | |SITE= | ||
| - | |LIGAND= <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene> | + | |LIGAND= <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> |
|ACTIVITY= | |ACTIVITY= | ||
|GENE= cTnC ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |GENE= cTnC ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[1aj4|1AJ4]] | ||
| + | |RESOURCES=<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://www.ebi.ac.uk/pdbsum/1ih0 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1ih0 RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==Overview== | ||
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. | 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. | ||
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| - | ==Disease== | ||
| - | Known diseases associated with this structure: Cardiomyopathy, dilated, 1Z OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191040 191040]], Cardiomyopathy, familial hypertrophic, 192600 (3) OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191040 191040]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Sykes, B D.]] | [[Category: Sykes, B D.]] | ||
[[Category: Wang, X.]] | [[Category: Wang, X.]] | ||
| - | [[Category: CA]] | ||
| - | [[Category: EMD]] | ||
[[Category: ca2+ binding protein]] | [[Category: ca2+ binding protein]] | ||
| - | [[Category: ca2+ sensitizer]] | + | [[Category: ca2+ sensitizer,]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 21:19:40 2008'' |
Revision as of 18:19, 30 March 2008
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| Ligands: | , | ||||||
| Gene: | cTnC (Homo sapiens) | ||||||
| Related: | 1AJ4
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| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Structure of the C-domain of Human Cardiac Troponin C in Complex with Ca2+ Sensitizer EMD 57033
Overview
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.
About this Structure
1IH0 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
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
Page seeded by OCA on Sun Mar 30 21:19:40 2008
