Motion and flexibility in human cytochrome p450 aromatase.
Motion and flexibility in human cytochrome p450 aromatase.
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DOI：
10.1371/journal.pone.0032565
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Ghosh D
中科院分区：
文献类型：
--
作者：
Jiang W;Ghosh D
与底物雄烯二酮和孕甾烷复合的人胎盘芳香化酶的晶体结构揭示了雄激素特异性活性位点和更高级组织的结构基础。然而，X射线结构并不提供由于短程波动、配体结合和蛋白质-蛋白质缔合而引起的运动的说明。在这项工作中，我们进行正常模式分析（NMA）揭示芳香化酶的内在波动，推导出内部模式的无膜和膜整合的单体以及低聚物的分子间模式，并提出了一个四级组织内质网（ER）膜整合。从NMA的结晶低聚物的动力学被发现是一致的各向同性的热因子从X射线分析。从它们的平衡位置的C-α原子的均方根波动的计算证实，芳香化酶的刚性核心结构是固有的，无论类固醇结合相互作用的变化，芳香化酶自缔合不恶化的刚性的催化裂缝。此外，NMA对膜整合芳香化酶显示，内部模式在所有的可能性有助于呼吸的活性位点接入通道。集体分子间铰链弯曲和扭曲模式提供了芳香酶低聚物的膜整合所需的四元缔合的灵活性。两者合计，波动的活性位点，通道，血红素近端腔，和一个动态的四级组织都可能是功能性芳香酶的重要组成部分，其作用作为ER膜嵌入类固醇生成酶。
The crystal structures of human placental aromatase in complex with the substrate androstenedione and exemestane have revealed an androgen-specific active site and the structural basis for higher order organization. However, X-ray structures do not provide accounts of movements due to short-range fluctuations, ligand binding and protein-protein association. In this work, we conduct normal mode analysis (NMA) revealing the intrinsic fluctuations of aromatase, deduce the internal modes in membrane-free and membrane-integrated monomers as well as the intermolecular modes in oligomers, and propose a quaternary organization for the endoplasmic reticulum (ER) membrane integration. Dynamics of the crystallographic oligomers from NMA is found to be in agreement with the isotropic thermal factors from the X-ray analysis. Calculations of the root mean square fluctuations of the C-alpha atoms from their equilibrium positions confirm that the rigid-core structure of aromatase is intrinsic regardless of the changes in steroid binding interactions, and that aromatase self-association does not deteriorate the rigidity of the catalytic cleft. Furthermore, NMA on membrane-integrated aromatase shows that the internal modes in all likelihood contribute to breathing of the active site access channel. The collective intermolecular hinge bending and twisting modes provide the flexibility in the quaternary association necessary for membrane integration of the aromatase oligomers. Taken together, fluctuations of the active site, the access channel, and the heme-proximal cavity, and a dynamic quaternary organization could all be essential components of the functional aromatase in its role as an ER membrane-embedded steroidogenic enzyme.
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影响因子：
2.9
作者：
DAVISON, SC;WILLS, ED
通讯作者：
WILLS, ED
影响因子：
4.8
作者：
Praporski, Slavica;Ng, Su May;Martin, Lisandra L.
通讯作者：
Martin, Lisandra L.
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1073/pnas.80.12.3696
发表时间：
1983-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
GO, N;NOGUTI, T;NISHIKAWA, T
通讯作者：
NISHIKAWA, T
DOI：
10.1073/pnas.0802496105
发表时间：
2008-07-29
影响因子：
11.1
作者：
Dobbins, Sara E.;Lesk, Victor I.;Sternberg, Michael J. E.
通讯作者：
Sternberg, Michael J. E.