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

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.
AuthorsY Li, M L Love, J A Putkey, C Cohen
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 97 Issue 10 Pg. 5140-5 (May 09 2000) ISSN: 0027-8424 [Print] United States
PMID10792039 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Troponin C
  • Troponin I
  • Bepridil
  • Calcium
Topics
  • Amino Acid Sequence
  • Animals
  • Bepridil (chemistry, metabolism, pharmacology)
  • Calcium (metabolism)
  • Chickens
  • Crystallization
  • Crystallography, X-Ray
  • Models, Molecular
  • Molecular Sequence Data
  • Myocardial Contraction
  • Myocardium (metabolism)
  • Protein Conformation
  • Protein Structure, Secondary
  • Troponin C (chemistry, drug effects)
  • Troponin I (chemistry, metabolism)

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