1lxf

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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

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

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, 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 with CA and BEP as ligands. 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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