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.
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Authors | Y Li, M L Love, J A Putkey, C Cohen |
Journal | Proceedings 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 |
PMID | 10792039
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Troponin C
- Troponin I
- Bepridil
- Calcium
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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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