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首页> 外文期刊>Journal of Molecular Biology >Conformational States of cytochrome p450cam revealed by trapping of synthetic molecular wires.
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Conformational States of cytochrome p450cam revealed by trapping of synthetic molecular wires.

机译：细胞色素p450cam的构象状态通过捕获合成分子丝揭示。

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Members of the ubiquitous cytochrome P450 family catalyze a vast range of biologically significant reactions in mammals, plants, fungi, and bacteria. Some P450s display a remarkable promiscuity in substrate recognition, while others are very specific with respect to substrate binding or regio and stereo-selective catalysis. Recent results have suggested that conformational flexibility in the substrate access channel of many P450s may play an important role in controlling these effects. Here, we report the X-ray crystal structures at 1.8A and 1.5A of cytochrome P450cam complexed with two synthetic molecular wires, D-4-Ad and D-8-Ad, consisting of a dansyl fluorophore linked to an adamantyl substrate analog via an alpha,omega-diaminoalkane chain of varying length. Both wires bind with the adamantyl moiety in similar positions at the camphor-binding site. However, each wire induces a distinct conformational response in the protein that differs from the camphor-bound structure. The changes involve significant movements of the F, G, and I helices, allowing the substrate access channel to adapt to the variable length of the probe. Wire-induced opening of the substrate channel also alters the I helix bulge and Thr252 at the active site with binding of water that has been proposed to assist in peroxy bond cleavage. The structures suggest that the coupling of substrate-induced conformational changes to active-site residues may be different in P450cam and recently described mammalian P450 structures. The wire-induced changes may be representative of the conformational intermediates that must exist transiently during substrate entry and product egress, providing a view of how substrates enter the deeply buried active site. They also support observed examples of conformational plasticity that are believed be responsible for the promiscuity of drug metabolizing P450s. Observation of such large changes in P450cam suggests that substrate channel plasticity is a general property inherent to all P450 structures.
机译：普遍存在的细胞色素P450家族的成员在哺乳动物，植物，真菌和细菌中催化多种生物学上重要的反应。一些P450在底物识别方面表现出明显的混杂性，而其他P450在底物结合或区域和立体选择性催化方面非常特异性。最近的结果表明，许多P450的底物进入通道中的构象柔性可能在控制这些效应中起重要作用。在这里，我们报告了细胞色素P450cam在1.8A和1.5A处的X射线晶体结构，该结构与两条合成分子线D-4-Ad和D-8-Ad络合，该分子线由通过金刚烷基底物类似物连接的丹磺酰基荧光团组成不同长度的α，ω-二氨基链烷烃链。两条线在樟脑结合位点的相似位置与金刚烷基部分结合。但是，每条线都在与樟脑结合的结构不同的蛋白质中诱导出独特的构象响应。这些变化涉及F，G和I螺旋的显着运动，从而使底物进入通道能够适应探针的可变长度。线诱导的底物通道的打开还通过结合水而改变了活性位点的I螺旋凸起和Thr252，已提出了水的结合以协助过氧键裂解。该结构表明底物诱导的构象变化与活性位点残基的偶联在P450cam和最近描述的哺乳动物P450结构中可能不同。线引起的变化可以代表在底物进入和产物流出期间必须瞬时存在的构象中间体，从而提供底物如何进入深埋的活性位点的视图。他们还支持观察到的构象可塑性实例，这些实例被认为是造成药物代谢P450混杂的原因。在P450cam中观察到如此大的变化表明，底物通道可塑性是所有P450结构固有的一般特性。

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