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Titolo:
Binding of levosimendan, a calcium sensitizer, to cardiac troponin C
Autore:
Sorsa, T; Heikkinen, S; Abbott, MB; Abusamhadneh, E; Laakso, T; Tilgmann, C; Serimaa, R; Annila, A; Rosevear, PR; Drakenberg, T; Pollesello, P; Kilpelainen, I;
Indirizzi:
Univ Helsinki, Inst Biotechnol, NMR Lab, FIN-00014 Helsinki, Finland Univ Helsinki Helsinki Finland FIN-00014 ab, FIN-00014 Helsinki, Finland Univ Cincinnati, Coll Med, Dept Mol Genet Biochem & Microbiol, Cincinnati,OH 45267 USA Univ Cincinnati Cincinnati OH USA 45267 icrobiol, Cincinnati,OH 45267 USA Univ Helsinki, Dept Phys, Xray Lab, FIN-00014 Helsinki, Finland Univ Helsinki Helsinki Finland FIN-00014 ab, FIN-00014 Helsinki, Finland Orion Pharm, Res & Dev, FIN-02101 Espoo, Finland Orion Pharm Espoo Finland FIN-02101 Res & Dev, FIN-02101 Espoo, Finland Univ Lund, Ctr Chem, Dept Phys Chem 2, S-22100 Lund, Sweden Univ Lund Lund Sweden S-22100 em, Dept Phys Chem 2, S-22100 Lund, Sweden VTT Biotechnol, FIN-00014 Helsinki, Finland VTT Biotechnol Helsinki Finland FIN-00014 l, FIN-00014 Helsinki, Finland
Titolo Testata:
JOURNAL OF BIOLOGICAL CHEMISTRY
fascicolo: 12, volume: 276, anno: 2001,
pagine: 9337 - 9343
SICI:
0021-9258(20010323)276:12<9337:BOLACS>2.0.ZU;2-G
Fonte:
ISI
Lingua:
ENG
Soggetto:
NUCLEAR-MAGNETIC-RESONANCE; HIGH-AFFINITY LIGANDS; REGULATORY DOMAIN; NMR; DRUG; PHOSPHORYLATION; SCATTERING; PROTEINS; BEPRIDIL; COMPLEX;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
33
Recensione:
Indirizzi per estratti:
Indirizzo: Kilpelainen, I Univ Helsinki, Inst Biotechnol, NMR Lab, POB 56, FIN-00014 Helsinki, Finland Univ Helsinki POB 56 Helsinki Finland FIN-00014 i, Finland
Citazione:
T. Sorsa et al., "Binding of levosimendan, a calcium sensitizer, to cardiac troponin C", J BIOL CHEM, 276(12), 2001, pp. 9337-9343

Abstract

Levosimendan is an inodilatory drug that mediates its cardiac effect by the calcium sensitization of contractile proteins. The target protein of levosimendan is cardiac troponin C (cTnC). In the current work, we have studiedthe interaction of levosimendan with Ca2+-saturated cTnC by heteronuclear NMR and small angle x-ray scattering. A specific interaction between levosimendan and the Ca2+-loaded regulatory domain of recombinant cTnC(C35C) was observed. The changes in the NMR spectra of the N-domain of full-length cTnC(C35S), due to the binding of levosimendan to the primary site, were indicative of a slow conformational exchange. In contrast, no binding of levosimendan to the regulatory domain of cTnC(A-Cys) where all the cysteine residues are mutated to serine, was detected. Moreover, it was shown that levosimendan was in fast exchange on the NMR time scale with a secondary binding site in the C-domain of both cTnC(C35S) and cTnC(A-Cys). The small angle x-ray scattering experiments confirm the binding of levosimendan to Ca2+-saturated cTnC but show no domain-domain closure. The experiments were run in the absence of the reducing agent dithiothreitol and the preservative sodium azide (NaN3), since we found that levosimendan reacts with these chemicals,commonly used for preparation of NMR protein samples.

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Documento generato il 24/11/20 alle ore 22:17:17