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

AUTOR(ES)

Li, Yu

FONTE

The National Academy of Sciences

RESUMO

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 Ca2+. We have determined the crystal structure of cTnC, with three bound Ca2+ ions, complexed with the calcium-sensitizer bepridil, to 2.15-Å resolution. In contrast to apo- and 3Ca2+-cTnC, the drug-bound complex displays a fully open N-terminal lobe similar to the N-terminal lobes of 4Ca2+-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 Ca2+-sensitizing effect of bepridil and reveal the details of a distinctive two-stage mechanism for Ca2+ regulation by troponin C in cardiac muscle.

Documentos Relacionados

• Sites of Intra- and Intermolecular Cross-linking of the N-terminal Extension of Troponin I in Human Cardiac Whole Troponin Complex*
• The mouse c-rel protein has an N-terminal regulatory domain and a C-terminal transcriptional transactivation domain.
• Deletion of an N-terminal regulatory domain of the c-abl tyrosine kinase activates its oncogenic potential.
• Distinct N-Terminal Regulatory Domains of Ca2+/H+ Antiporters1
• The N-terminal to C-terminal motif in protein folding and function