Bernardi Francesca, D'Amelio Nicola, Gaggelli Elena, Molteni Elena, Valensin Gianni
Department of Chemistry and the NMR Center, University of Siena, Via A. Moro, 53100 Siena, Italy.
J Phys Chem B. 2008 Jan 24;112(3):828-35. doi: 10.1021/jp076837z. Epub 2007 Dec 21.
Cyclosporin A (CsA) is a cyclic naturally occurring peptide used to prevent graft rejection in organ transplantations. Its immunosuppressive activity is due to the formation of a complex with cyclophilin A (Cyp), in which the cis 9MeLeu-10MeLeu amide bond of CsA assumes a trans conformation. The mechanism of the conformational inversion has not been delineated, but it has been postulated that metal ions binding induces a conformational change that enables CsA to bind Cyp. In this work, we solved the structures of CsA in sodium dodecyl sulfate (SDS) micelles (which enhance its solubility and mimic the hydrophobic environment clinically used for drug delivery) and its complex with Dy(III) ion, whose coordination chemistry is frequently used to reproduce the effect of Ca(II). The paramagnetic properties of Dy(III) allowed us to build up a structure using proton relaxation enhancements, which remains stable in a MD simulation in the micelle environment.
环孢素A（CsA）是一种天然存在的环状肽，用于预防器官移植中的移植排斥反应。其免疫抑制活性归因于与亲环蛋白A（Cyp）形成复合物，其中CsA的顺式9MeLeu-10MeLeu酰胺键呈现反式构象。构象反转的机制尚未阐明，但据推测金属离子结合会诱导构象变化，使CsA能够结合Cyp。在这项工作中，我们解析了CsA在十二烷基硫酸钠（SDS）胶束中的结构（SDS胶束可提高其溶解度并模拟临床上用于药物递送的疏水环境）以及它与Dy（III）离子的复合物结构，Dy（III）的配位化学常用于重现Ca（II）的作用。Dy（III）的顺磁性质使我们能够利用质子弛豫增强来构建结构，该结构在胶束环境的分子动力学模拟中保持稳定。
