Zanotti G, Falcigno L, Saviano M, D'Auria G, Bruno B M, Campanile T, Paolillo L
Dipartimento di Chimcia, Università di Napoli Federico II, Complesso Universitario Monte S. Angelo, Italy.
Chemistry. 2001 Apr 1;7(7):1479-85. doi: 10.1002/1521-3765(20010401)7:7<1479::aid-chem1479>3.0.co;2-2.
Phallotoxins are toxic compounds produced by poisonous mushroom Amanita phalloides and belong to the class of bicyclic peptides with a transannular thioether bridge. Their intoxication mechanism in the liver involves a specific binding of the toxins to F-actin that, consequently, prevents the depolymerization equilibrium with G-actin. Even though the conformational features of phallotoxins have been worked out in solution, the exact mechanism of interaction with F-actin is still unknown. In this study a toxic phalloidin synthetic derivative, bicyclo(Ala1-D-Thr2-Cys3-cis-4-hydroxy-Pro4-Ala5-2-mercapto-Trp6-Ala7)(S-3-->6) has been synthesized. A substitution at position 7. with an Ala residue replaces the 4,5-dihydroxy-Leu present in the natural phalloidin. This analogue has formed crystals suitable for X-ray analysis, and represents the first case for such a class of compounds. The solid-state structure as well as the solution conformation have been evaluated. NMR techniques have been used to extract interproton distances as restraints in subsequent molecular dynamics calculations. Finally, a direct comparison between structures in solution and in the solid state is presented.
鬼笔毒素是由毒蘑菇毒鹅膏产生的有毒化合物，属于具有跨环硫醚桥的双环肽类。它们在肝脏中的中毒机制涉及毒素与F-肌动蛋白的特异性结合，从而阻止了与G-肌动蛋白的解聚平衡。尽管鬼笔毒素的构象特征已在溶液中得到阐明，但与F-肌动蛋白相互作用的确切机制仍然未知。在本研究中，合成了一种有毒的鬼笔环肽合成衍生物，双环（Ala1-D-Thr2-Cys3-顺式-4-羟基-Pro4-Ala5-2-巯基-Trp6-Ala7）（S-3→6）。在第7位用丙氨酸残基取代，取代了天然鬼笔环肽中存在的4,5-二羟基亮氨酸。该类似物已形成适合X射线分析的晶体，代表了此类化合物的首例。已评估了固态结构以及溶液构象。核磁共振技术已被用于提取质子间距离，作为后续分子动力学计算的限制条件。最后，对溶液和固态中的结构进行了直接比较。
