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Study on structure of cytochrome b using antimycin A-resistant mutants.

利用抗霉素A突变体研究细胞色素b的结构。

基本信息

批准号：
06660132
负责人：
MIYOSHI Hideto
金额：
$ 1.28万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1995
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06660132/
关键词：
mitochondria cytochrome bcl antimycin A シトクロムbc,アンチマイシンシトクロムb

项目摘要

The structural factors of antimycin A molecule requred for inhibitory action were studied using newly synthesized antimycin A derivatives with bovine heart submitochondrial particles, in order to probe the interaction between antimycin A and its binding site. In particular, we focussed upon the roles of the amide bond bridge, which connects the salicylic acid and dilactone-ring moieties, and the 3-formylamino group in the salicylic acid moiety. The lack of formation of an intramolecular hydrogen-bond between phenolic OH and amide carbonyl groups resulted in a remarkable loss of the activity (by four orders of magnitude), indicating that this hydrogen-bond is essential for the inhibition. This result suggested that both the phenolic OH and the carbonyl groups form a hydrogen-bond with some residues at a fixed conformation. In addition, the inhibitory potency was remarkably decreased by N-methylation of the amide bond moiety, indicating that the NH group might function in hydrogen-bond interaction with the binding site. The N-methylation of 3-formylamino group also resulted in a decrease in the activity, probably due to a loss of the rotational freedom of this functional group. Molecular orbital calculation studies with respect to the conformation of the 3-formylamino group indicated that this group takes an active conformation when the formyl carbonyl projects to the opposite side of the phenolic OH group. Based upon a series of structure-activity studies of synthetic antimycin A analogues, we propose a tentative model for antimycin A binding in its binding cavity.

用新合成的抗霉素A衍生物与牛心亚线粒体颗粒结合，研究了抑制作用所需的抗霉素A分子结构因素，以探讨抗霉素A与其结合位点的相互作用。特别是，我们集中在酰胺键桥，连接水杨酸和双内酯环部分，和3-甲酰氨基基团中的水杨酸部分的作用。酚羟基和酰胺羰基之间的分子内氢键的形成的缺乏导致了显着的损失的活动（由四个数量级），表明这种氢键是必不可少的抑制。这一结果表明，酚羟基和羰基都与某些构象固定的残基形成氢键。此外，抑制效力显着降低的酰胺键部分的N-甲基化，表明NH基团可能与结合位点的氢键相互作用。3-甲酰氨基的N-甲基化也导致活性降低，可能是由于该官能团的旋转自由度的丧失。分子轨道计算的构象的3-甲酰氨基基团的研究表明，这个组采取积极的构象时，甲酰基羰基项目的酚OH基团的相对侧。基于对合成的抗霉素A类似物的一系列构效关系的研究，我们提出了抗霉素A在其结合腔中结合的初步模型。