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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >An open conformation of mammalian cytochrome P450 2B4 at 1.6-A resolution
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An open conformation of mammalian cytochrome P450 2B4 at 1.6-A resolution

机译：哺乳动物细胞色素P450 2B4的开放构象，分辨率为1.6-A

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摘要

The xenobiotic metabolizing cytochromes P450 (P450s) are among the most versatile biological catalysts known, but knowledge of the structural basis for their broad substrate specificity has been limited. P450 2B4 has been frequently used as an experimental model for biochemical and biophysical studies of these membrane proteins. A 1.6-A crystal structure of P450 2B4 reveals a large open cleft that extends from the protein surface directly to the heme iron between the α-helical and β-sheet domains without perturbing the overall P450 fold. This cleft is primarily formed by helices B' to C and F to G. The conformation of these regions is dramatically different from that of the other structurally defined mammalian P450, 2C5/3LVdH, in which the F to G and B' to C regions encapsulate one side of the active site to produce a closed form of the enzyme. The open conformation of 2B4 is trapped by reversible formation of a homodimer in which the residues between helices F and G of one molecule partially fill the open cleft of a symmetry-related molecule, and an intermolecular coordinate bond occurs between H226 and the heme iron. This dimer is observed both in solution and in the crystal. Differences between the structures of 2C5 and 2B4 suggest that defined regions of xenobiotic metabolizing P450s may adopt a substantial range of energetically accessible conformations without perturbing the overall fold. This conformational flexibility is likely to facilitate substrate access, metabolic versatility, and product egress.
机译：异种生物代谢细胞色素P450（P450s）是已知的用途最广泛的生物催化剂，但是其广泛的底物特异性的结构基础知识有限。 P450 2B4经常被用作这些膜蛋白的生化和生物物理研究的实验模型。 P450 2B4的1.6-A晶体结构揭示了一个大的开放裂缝，该裂缝从蛋白质表面直接延伸到α-螺旋结构域和β-折叠结构域之间的血红素铁，而不会干扰整个P450折叠。这种裂痕主要是由B'至C和F至G螺旋形成的。这些区域的构象与其他结构限定的哺乳动物P450、2C5 / 3LVdH的构象显着不同，其中F至G和B'至C区域包裹活性位点的一侧以产生封闭形式的酶。 2B4的开放构象被同二聚体的可逆形成捕获，其中一个分子的螺旋F和G之间的残基部分填充了对称相关分子的开放裂隙，并且在H226和血红素铁之间发生了分子间配位键。在溶液和晶体中均观察到该二聚体。 2C5和2B4的结构之间的差异表明，异源生物代谢P450的定义区域可能采用大量能量可及的构象，而不会干扰整体折叠。这种构象上的灵活性可能会促进底物的进入，代谢的多样性和产物的流出。

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