1dtl
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CRYSTAL STRUCTURE OF CALCIUM-SATURATED (3CA2+) CARDIAC TROPONIN C COMPLEXED WITH THE CALCIUM SENSITIZER BEPRIDIL AT 2.15 A RESOLUTION
OverviewOverview
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.
About this StructureAbout this Structure
1DTL is a Single protein structure of sequence from Gallus gallus with and as ligands. Full crystallographic information is available from OCA.
ReferenceReference
Bepridil opens the regulatory N-terminal lobe of cardiac troponin C., Li Y, Love ML, Putkey JA, Cohen C, Proc Natl Acad Sci U S A. 2000 May 9;97(10):5140-5. PMID:10792039
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