Conformational change in ricin toxin A-Chain: A critical factor for inhibitor binding to the secondary pocket
Conformational change in ricin toxin A-Chain: A critical factor for inhibitor binding to the secondary pocket
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DOI：
10.1016/j.bbrc.2022.08.008
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发表时间：
2022-08-20
影响因子：
3.1
通讯作者：
Saito, Ryota
中科院分区：
文献类型：
--
作者：
Goto, Masaru;Higashi, Shoko;Saito, Ryota
蓖麻毒素 A 链 (RTA) 是一种来自蓖麻的有毒蛋白质，可灭活核糖体以诱导毒性。 RTA 的活性位点由两个结合口袋组成。许多研究都集中在开发可以同时与这些关键口袋结合的 RTA 抑制剂；然而，迄今为止开发的几乎所有抑制剂仅与一个口袋相互作用。在本研究中，我们发现带有芳香族L-氨基酸侧垂的蝶呤-7-甲酰胺以2对1的模式与酶的活性位点相互作用，其中一个抑制剂分子与初级口袋结合，第二个抑制剂分子进入RTA活性位点的次级口袋。抑制剂/RTA 复合物的 X 射线晶体分析表明，RTA 中 Tyr80 和 Asn122 的构象变化对于触发抑制剂分子进入 RTA 活性位点的二级口袋至关重要。(C) 2022 Elsevier Inc. 保留所有权利。
Ricin toxin A-chain (RTA), a toxic protein from Ricinus communis, inactivates ribosomes to induce toxicity. The active site of RTA consists of two binding pockets. Many studies have focused on developing RTA inhibitors that can simultaneously bind to these critical pockets; however, almost all the inhibitors developed so far interact with only one pocket. In the present study, we discovered that pterin-7-carboxamides with aromatic L-amino acid pendants interacted with the active site of the enzyme in a 2-to-1 mode, where one inhibitor molecule bound to the primary pocket and the second one entered the secondary pocket in the active site of RTA. X-ray crystallographic analysis of inhibitor/RTA complexes revealed that the conformational changes of Tyr80 and Asn122 in RTA were critical for triggering the entry of inhibitor molecules into the secondary pocket of the RTA active site.(C) 2022 Elsevier Inc. All rights reserved.