Crystal structure of human cytochrome P450 2D6
Crystal structure of human cytochrome P450 2D6
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DOI：
10.1074/jbc.m511232200
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发表时间：
2006-03-17
影响因子：
4.8
通讯作者：
Bridges, AM
中科院分区：
文献类型：
--
作者：
Rowland, P;Blaney, FE;Bridges, AM
细胞色素P450 2D6是一种含血红素的酶，负责至少20%的已知药物的代谢。2D6的底物通常含有碱性氮和平面芳环。人类2D6的晶体结构已被解决并细化到3.0埃分辨率。该结构显示了家族其他成员中所见的特征性P450折叠，单个二级结构元件的长度和方向与2C9中所见的非常相似。然而，有几个重要的差异，最值得注意的涉及F螺旋，F-G环，B '螺旋，β折叠4和部分β折叠1，所有这些都位于蛋白质的远端。2D6结构在血红素基团上方具有明确的活性位点空腔，含有许多参与底物识别和结合的重要残基，包括Asp-301、Glu-216、Phe-483和Phe-120。晶体结构有助于解释Asp-301，Glu-216和Phe-483如何作为底物结合残基，并表明Phe-120的作用是控制大多数底物中发现的芳香环相对于血红素的方向。该结构已与已发表的同源模型进行了比较，并已被用来解释许多报道的定点诱变数据，并帮助了解几种化合物的代谢。
Cytochrome P450 2D6 is a heme-containing enzyme that is responsible for the metabolism of at least 20% of known drugs. Substrates of 2D6 typically contain a basic nitrogen and a planar aromatic ring. The crystal structure of human 2D6 has been solved and refined to 3.0 angstrom resolution. The structure shows the characteristic P450 fold as seen in other members of the family, with the lengths and orientations of the individual secondary structural elements being very similar to those seen in 2C9. There are, however, several important differences, the most notable involving the F helix, the F-G loop, the B' helix, beta sheet 4, and part of beta sheet 1, all of which are situated on the distal face of the protein. The 2D6 structure has a well defined active site cavity above the heme group, containing many important residues that have been implicated in substrate recognition and binding, including Asp-301, Glu-216, Phe-483, and Phe-120. The crystal structure helps to explain how Asp-301, Glu-216, and Phe-483 can act as substrate binding residues and suggests that the role of Phe-120 is to control the orientation of the aromatic ring found in most substrates with respect to the heme. The structure has been compared with published homology models and has been used to explain much of the reported site-directed mutagenesis data and help understand the metabolism of several compounds.