Structure-based identification of a ricin inhibitor
Structure-based identification of a ricin inhibitor
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DOI：
10.1006/jmbi.1996.0865
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发表时间：
1997-03-14
影响因子：
5.6
通讯作者：
Robertus, JD
中科院分区：
文献类型：
--
作者：
Yan, XJ;Hollis, T;Robertus, JD
蓖麻毒素是一种有效的细胞毒素，已被广泛用于构建治疗剂，如免疫毒素。最近，它被政府和地下组织用作毒药。人们对鉴定和设计蓖麻毒素A链（RTA）的有效抑制剂很感兴趣。在这项研究中，计算机辅助搜索表明，蝶呤可能结合在RTA活性位点，通常识别rRNA上的特定腺嘌呤碱基。动力学分析表明，蝶酸可以抑制RTA活性，表观Ki为0.6 mM。该复合物的2.3埃晶体结构揭示了结合模式。蝶呤环取代Tyr 80并结合在腺嘌呤口袋中，与活性位点残基形成特异性氢键。蝶酸的苯甲酸酯部分结合在Tyr 80的相对侧上，使货车德瓦尔斯与Tyr环接触并与Asn 78形成氢键。新蝶呤是蝶呤的丙烷三醇衍生物，也与RTA结合，如其与RTA的复合物的X射线结构所揭示的。蝶呤-6-羧酸和叶酸都不与晶体结合或作为抑制剂。观察到的模型表明蝶呤部分的改变，这可能产生更有效和特异性的RTA抑制剂。(C)出版社：Academic Press Limited。
Ricin is a potent cytotoxin which has been used widely in the construction of therapeutic agents such as immunotoxins. Recently it has been used by governments and underground groups as a poison. There is interest in identifying and designing effective inhibitors of the ricin A chain (RTA). In this study computer-assisted searches indicated that pterins might bind in the RTA active site which normally recognizes a specific adenine base on rRNA. Kinetic assays showed that pteroic acid could inhibit RTA activity with an apparent K-i of 0.6 mM. A 2.3 Angstrom crystal structure of the complex revealed the mode of binding. The pterin ring displaces Tyr80 and binds in the adenine pocket making specific hydrogen bonds to active site residues. The benzoate moiety of pteroic acid binds on the opposite side of Tyr80 making van der Waals contact with the Tyr ring and forming a hydrogen bond with Asn78. Neopterin, a propane triol derivative of pterin, also binds to RTA as revealed by the X-ray structure of its complex with RTA. Neither pterin-6-carboxylic acid nor folic acid bind to the crystal or act as inhibitors. The models observed suggest alterations to the pterin moiety which may produce more potent and specific RTA inhibitors. (C) 1997 Academic Press Limited.