Pollesello P, Ovaska M, Kaivola J, Tilgmann C, Lundström K, Kalkkinen N, Ulmanen I, Nissinen E, Taskinen J
Orion Corp., Orion-Farmos, Orion Research, Espoo, Finland.
J Biol Chem. 1994 Nov 18;269(46):28584-90.
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.
本文描述了一种新型钙敏化剂左西孟旦与人心脏肌钙蛋白C（cTnC）的结合情况。对丹磺酰化重组人cTnC和一个定点突变体进行的荧光研究表明，左西孟旦可调节cTnC中钙诱导的构象变化，并揭示了Asp-88在药物与cTnC氨基末端结构域结合中的作用。此外，对cTnC氨基末端片段进行的核磁共振研究显示，在药物-蛋白质复合物中，左西孟旦与Met81、Met85和Phe77在空间上接近。这些数据被用于构建药物-蛋白质复合物的优化模型，其中左西孟旦在氨基末端结构域的疏水口袋处与cTnC结合。文中还讨论了左西孟旦与cTnC结合在该药物体内药理作用中的作用。
