Department of Chemistry, Faculty of Science, Toho University, Funabashi, Chiba, Japan.
Research Center for Materials with Integrated Properties, Toho University, Funabashi, Chiba, Japan.
PLoS One. 2022 Dec 12;17(12):e0277770. doi: 10.1371/journal.pone.0277770. eCollection 2022.
The Ricin toxin A chain (RTA), which depurinates an adenine base at a specific region of the ribosome leading to death, has two adjacent specificity pockets in its active site. Based on this structural information, many attempts have been made to develop small-molecule RTA inhibitors that simultaneously block the two pockets. However, no attempt has been successful. In the present study, we synthesized pterin-7-carboxamides with tripeptide pendants and found that one of them interacts with both pockets simultaneously to exhibit good RTA inhibitory activity. X-ray crystallographic analysis of the RTA crystal with the new inhibitor revealed that the conformational change of Tyr80 is an important factor that allows the inhibitors to plug the two pockets simultaneously.
蓖麻毒素 A 链 (RTA) 能够使核糖体特定区域的腺嘌呤碱基脱嘌呤，从而导致细胞死亡，其活性位点有两个相邻的特异性结合口袋。基于这一结构信息，人们已经尝试了许多方法来开发同时阻断两个口袋的小分子 RTA 抑制剂。然而，这些尝试都没有成功。在本研究中，我们合成了带有三肽侧链的蝶呤-7-甲酰胺，并发现其中一种抑制剂能够同时与两个口袋相互作用，表现出良好的 RTA 抑制活性。与新型抑制剂的 RTA 晶体的 X 射线晶体学分析表明， Tyr80 的构象变化是允许抑制剂同时插入两个口袋的重要因素。
