NDLI: Bepridil opens the regulatory N-terminal lobe of cardiac troponin C

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Bepridil opens the regulatory N-terminal lobe of cardiac troponin C

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Bepridil opens the regulatory N-terminal lobe of cardiac troponin C

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Li, Y. Cohen, C. Putkey, J. A. Love, M. L.
Description	Author Affiliation: Li Y ( Biophysics and Structural Biology Program, Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA 02454-9110, USA.);
Abstract	Cardiac troponin C (cTnC) is the calcium-dependent switch for contraction in heart muscle and a potential target for drugs in the therapy of congestive heart failure. This calmodulin-like protein consists of two lobes connected by a central linker; each lobe contains two EF-hand domains. The regulatory N-terminal lobe of cTnC, unlike that of skeletal troponin C (sTnC), contains only one functional EF-hand and does not open fully upon the binding of Ca(2+). We have determined the crystal structure of cTnC, with three bound Ca(2+) ions, complexed with the calcium-sensitizer bepridil, to 2.15-A resolution. In contrast to apo- and 3Ca(2+)-cTnC, the drug-bound complex displays a fully open N-terminal lobe similar to the N-terminal lobes of 4Ca(2+)-sTnC and cTnC bound to a C-terminal fragment of cardiac troponin I (residues 147-163). The closing of the lobe is sterically hindered by one of the three bound bepridils. Our results provide a structural basis for the Ca(2+)-sensitizing effect of bepridil and reveal the details of a distinctive two-stage mechanism for Ca(2+) regulation by troponin C in cardiac muscle.
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	10
Volume Number	97
Language	English
Publisher	National Academy of Sciences
Publisher Date	2000-06-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Bepridil Chemistry Pharmacology Myocardium Metabolism Troponin C Drug Effects Amino Acid Sequence Animals Calcium Crystallization Crystallography, X-Ray Models, Molecular Molecular Sequence Data Myocardial Contraction Protein Conformation Protein Structure, Secondary Troponin I Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. Multidisciplinary
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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