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1lxf

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[[Image:1lxf.gif|left|200px]]
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{{STRUCTURE_1lxf| PDB=1lxf | SCENE= }}
{{STRUCTURE_1lxf| PDB=1lxf | SCENE= }}
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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'''
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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===
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==Overview==
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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.
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{{ABSTRACT_PUBMED_12060657}}
==About this Structure==
==About this Structure==
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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].
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1LXF is a [[Protein complex]] structure of sequences from [http://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].
==Reference==
==Reference==
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[[Category: Cardiac troponin i-drug interaction]]
[[Category: Cardiac troponin i-drug interaction]]
[[Category: Muscle]]
[[Category: Muscle]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 00:23:54 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jul 2 22:45:44 2008''

Revision as of 19:45, 2 July 2008

Image:1lxf.png

Template:STRUCTURE 1lxf

Structure of the Regulatory N-domain of Human Cardiac Troponin C in Complex with Human Cardiac Troponin-I(147-163) and Bepridil

Template:ABSTRACT PUBMED 12060657

About this Structure

1LXF is a Protein complex structure of sequences from Homo sapiens. Full experimental 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

Page seeded by OCA on Wed Jul 2 22:45:44 2008

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