The calcium sensitizer drug MCI-154 binds the structural C-terminal domain of cardiac troponin C.

The compound MCI-154 was previously shown to increase the calcium sensitivity of cardiac muscle contraction. Using solution NMR spectroscopy, we demonstrate that MCI-154 interacts with the calcium-sensing subunit of the cardiac troponin complex, cardiac troponin C (cTnC). Surprisingly, however, it binds only to the structural C-terminal domain of cTnC (cCTnC), and not to the regulatory N-terminal domain (cNTnC) that determines the calcium sensitivity of cardiac muscle.

One-Pot Generation of Bicyclo[3.1.0]hexanols and Cyclohexanones by Double Interrupted Nazarov Reactions.

Organoaluminum-mediated double interrupted Nazarov cyclization to access bicyclo[3.1.0]hexanols via nucleophilic methyl attack followed by Simmons-Smith-type electrophilic cyclopropanation is reported.

Structures reveal details of small molecule binding to cardiac troponin.

In cardiac and skeletal muscle, the troponin complex turns muscle contraction on and off in a calcium-dependent manner. Many small molecules are known to bind to the troponin complex to modulate its calcium binding affinity, and this may be useful in a broad range of conditions in which striated muscle function is compromised, such as congestive heart failure. As a tool for developing drugs specific for the cardiac isoform of troponin, we have designed a chimeric construct (cChimera) consisting of the regulatory N-terminal domain of cardiac troponin C (cNTnC) fused to the switch region of cardiac troponin I (cTnI), mimicking the key binding event that turns on muscle contraction.