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首页> 美国卫生研究院文献>Proceedings of the National Academy of Sciences of the United States of America >Crystal structures of substrate-bound and substrate-free cytochrome P450 46A1 the principal cholesterol hydroxylase in the brain
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Crystal structures of substrate-bound and substrate-free cytochrome P450 46A1 the principal cholesterol hydroxylase in the brain

机译：底物结合和无底物细胞色素P450 46A1（大脑中的主要胆固醇羟化酶）的晶体结构

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摘要

By converting cholesterol to 24S-hydroxycholesterol, cytochrome P450 46A1 (CYP46A1) initiates the major pathway for cholesterol removal from the brain. Two crystal structures of CYP46A1 were determined. First is the 1.9-Å structure of CYP46A1 complexed with a high-affinity substrate cholesterol 3-sulfate (CH-3S). The second structure is that of the substrate-free CYP46A1 at 2.4-Å resolution. CH-3S is bound in the productive orientation and occupies the entire length of the banana-shaped hydrophobic active-site cavity. A unique helix B′–C loop insertion (residues 116–120) contributes to positioning cholesterol for oxygenation catalyzed by CYP46A1. A comparison with the substrate-free structure reveals substantial substrate-induced conformational changes in CYP46A1 and suggests that structurally distinct compounds could bind in the enzyme active site. In vitro assays were performed to characterize the effect of different therapeutic agents on cholesterol hydroxylase activity of purified full-length recombinant CYP46A1, and several strong inhibitors and modest coactivators of CYP46A1 were identified. Structural and biochemical data provide evidence that CYP46A1 activity could be altered by exposure to some therapeutic drugs and potentially other xenobiotics.
机译：通过将胆固醇转化为24S-羟基胆固醇，细胞色素P450 46A1（CYP46A1）启动了从大脑清除胆固醇的主要途径。确定了CYP46A1的两个晶体结构。首先是CYP46A1的1.9-Å结构与高亲和性底物胆固醇3-硫酸盐（CH-3S）形成复合物。第二种结构是无底物的CYP46A1的2.4-Å分辨率。 CH-3S沿生产方向结合，并占据了香蕉形疏水活性部位空腔的整个长度。独特的螺旋B'–C环插入（残基116-120）有助于将胆固醇定位为被CYP46A1催化的氧合。与无底物结构的比较显示，CYP46A1发生了底物诱导的构象变化，表明结构上不同的化合物可以在酶活性位点结合。进行体外试验以表征不同治疗剂对纯化的全长重组CYP46A1的胆固醇羟化酶活性的影响，并鉴定了CYP46A1的几种强抑制剂和适度共激活因子。结构和生化数据提供证据表明，CYP46A1活性可能因暴露于某些治疗药物和潜在的其他异质生物而改变。

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