1lxf
From Proteopedia
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| - | [[Image:1lxf.gif|left|200px]]< | + | [[Image:1lxf.gif|left|200px]] |
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| - | '''Structure of the Regulatory N-domain of Human Cardiac Troponin C in Complex with Human Cardiac Troponin-I(147-163) and Bepridil''' | + | {{Structure |
| + | |PDB= 1lxf |SIZE=350|CAPTION= <scene name='initialview01'>1lxf</scene> | ||
| + | |SITE= | ||
| + | |LIGAND= <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene> and <scene name='pdbligand=BEP:1-ISOBUTOXY-2-PYRROLIDINO-3[N-BENZYLANILINO] PROPANE'>BEP</scene> | ||
| + | |ACTIVITY= | ||
| + | |GENE= TNNC ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
| + | }} | ||
| + | |||
| + | '''Structure of the Regulatory N-domain of Human Cardiac Troponin C in Complex with Human Cardiac Troponin-I(147-163) and Bepridil''' | ||
| + | |||
==Overview== | ==Overview== | ||
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==Disease== | ==Disease== | ||
| - | 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]] | + | Known diseases associated with this structure: Cardiomyopathy, dilated, 1Z OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191040 191040]], Cardiomyopathy, dilated, 2A OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191044 191044]], 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== | ==About this Structure== | ||
| - | 1LXF is a [ | + | 1LXF is a [[Protein complex]] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1LXF OCA]. |
==Reference== | ==Reference== | ||
| - | 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:// | + | 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://www.ncbi.nlm.nih.gov/pubmed/12060657 12060657] |
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
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[[Category: muscle]] | [[Category: muscle]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 12:36:21 2008'' |
Revision as of 10:36, 20 March 2008
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| Ligands: | and | ||||||
| Gene: | TNNC (Homo sapiens) | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Structure of the Regulatory N-domain of Human Cardiac Troponin C in Complex with Human Cardiac Troponin-I(147-163) and Bepridil
Contents |
Overview
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
Known diseases associated with this structure: Cardiomyopathy, dilated, 1Z OMIM:[191040], Cardiomyopathy, dilated, 2A OMIM:[191044], Cardiomyopathy, familial hypertrophic OMIM:[191044], Cardiomyopathy, familial hypertrophic, 192600 (3) OMIM:[191040], Cardiomyopathy, familial restrictive OMIM:[191044]
About this Structure
1LXF is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
Reference
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
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