Binding of a new Ca2+ sensitizer, levosimendan, to recombinant human cardiac troponin C: A molecular modelling, fluorescence probe, and proton nuclear magnetic resonance study

Research output: Contribution to journalArticle

Abstract

The binding of a new calcium sensitizer, levosimendan, to human cardiac troponin C (cTnC) is described. Fluorescence studies done on dansylated recombinant human cTnC and a site-directed mutant showed that levosimendan modulated the calcium-induced conformational change in cTnC, and revealed the role of Asp-88 in the binding of the drug to the NH2-terminal domain of cTnC. Furthermore, NMR studies performed on the NH2-terminal fragment of cTnC showed a spatial proximity between levosimendan and Met81, Met85, and Phe77 in the drug-protein complex. These data were used to build an optimized model of the drug-protein complex, in which levosimendan binds cTnC at the hydrophobic pocket of the NH2-terminal domain. The role of the binding of levosimendan to cTnC in the pharmacological action of this drug in vivo is discussed.

Details

Authors
  • Piero Pollesello
  • Martti Ovaskai
  • Juha Kaivola
  • Carola Tilgmann
  • Kenneth Lundström
  • Nisse Kalkkinen
  • Ismo Ulmanen
  • Erkki Nissinen
  • Jyrki Taskinen
External organisations
  • Orion Corporation
  • University of Helsinki
Original languageEnglish
Pages (from-to)28584-28590
Number of pages7
JournalJournal of Biological Chemistry
Volume269
Issue number46
Publication statusPublished - 1994 Nov 18
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes