Reversible Covalent Binding to Cardiac Troponin C by the Ca2+-Sensitizer Levosimendan

Ian M. Robertson, Sandra E. Pineda-Sanabria, Ziqian Yan, Thomas Kampourakis, Yin-Biao Sun, Brian D. Sykes, Malcolm Irving

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)


The binding of Ca2+ to cardiac troponin C (cTnC) triggers contraction in heart muscle. In the diseased heart, the
myocardium is often desensitized to Ca2+, which leads to impaired contractility. Therefore, compounds that sensitize cardiac
muscle to Ca2+ (Ca2+-sensitizers) have therapeutic promise. The only Ca2+-sensitizer used regularly in clinical settings is
levosimendan. While the primary target of levosimendan is thought to be cTnC, the molecular details of this interaction are not
well understood. In this study, we used mass spectrometry, computational chemistry, and nuclear magnetic resonance
spectroscopy to demonstrate that levosimendan reacts specifically with cysteine 84 of cTnC to form a reversible thioimidate
bond. We also showed that levosimendan only reacts with the active, Ca2+-bound conformation of cTnC. Finally, we propose a
structural model of levosimendan bound to cTnC, which suggests that the Ca2+-sensitizing function of levosimendan is due to
stabilization of the Ca2+-bound conformation of cTnC.
Original languageEnglish
Pages (from-to)6032-6045
Number of pages14
Issue number43
Early online date27 Sept 2016
Publication statusPublished - Nov 2016

Cite this