Distortion of flavin geometry is linked to ligand binding in cholesterol oxidase
Distortion of flavin geometry is linked to ligand binding in cholesterol oxidase
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DOI：
10.1110/ps.073168207
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发表时间：
2007-12-01
期刊：
影响因子：
8
通讯作者：
Vrielink, Alice
中科院分区：
文献类型：
--
作者：
Lyubimov, Artem Y.;Heard, Kathryn;Vrielink, Alice
两个高分辨率的结构的细菌胆固醇氧化酶的双突变体的存在或不存在的配体，甘油，提出，显示的轨迹甘油，因为它结合在米氏络合物样的位置在活性位点。一组三个芳香族残基迫使氧化的异咯嗪部分沿着N5-N10轴弯曲，作为对活性位点中甘油结合的响应。这些芳香族残基的运动只观察到在甘油结合的结构，表明一些调整的FAD氧化还原电位是由形成的米氏络合物在定期催化。这种结构的研究表明，底物辅助黄素活化的可能机制，提高了我们的理解之间的相互作用的酶，其黄素辅因子和其基板，并用于未来设计的有效的胆固醇氧化酶抑制剂。
Two high-resolution structures of a double mutant of bacterial cholesterol oxidase in the presence or absence of a ligand, glycerol, are presented, showing the trajectory of glycerol as it binds in a Michaelis complex-like position in the active site. A group of three aromatic residues forces the oxidized isoalloxazine moiety to bend along the N5-N10 axis as a response to the binding of glycerol in the active site. Movement of these aromatic residues is only observed in the glycerol-bound structure, indicating that some tuning of the FAD redox potential is caused by the formation of the Michaelis complex during regular catalysis. This structural study suggests a possible mechanism of substrate-assisted flavin activation, improves our understanding of the interplay between the enzyme, its flavin cofactor and its substrate, and is of use to the future design of effective cholesterol oxidase inhibitors.