Crystallographic analysis of the regulatory domain of human cardiac troponin C

The N-terminal regulatory domain of cardiac troponin C (N-cTnC) is an essential Ca2+ sensor to trigger muscle contraction. Using X-ray crystallography, the first crystal structure of wild type human N-cTnC was solved to 2.2 Å resolution. It revealed two novel features about this protein. First, each EF-hand binding loop coordinates two cadmium ions, even though one of the loops is normally inactive. One Cd2+ ion occupies the canonical ion binding site, whereas the other Cd2+ ion binds adjacent to it. Thus, N-cTnC is forced to adopt a very unusual conformation. Second, an additive, deoxycholic acid (DXC), was observed bound to the central hydrophobic cavity and between helix N and helix A. DXC has a similar chemical structure to Ca2+-sensitizing drugs that are used for treating troponin-related cardiovascular diseases. These new insights provide valuable information for the use of N-cTnC as a potential target for rational drug design.