Structural rationalization of novel drug metabolizing mutants of cytochrome P450 BM3
Structural rationalization of novel drug metabolizing mutants of cytochrome P450 BM3
复制标题
细胞色素P450 BM3新型药物代谢突变体的结构合理化
DOI：
--
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
C. Oostenbrink
中科院分区：
文献类型：
--
作者：
Eva Stjernschantz;B. V. van Vugt;A. Bonifacio;Stephanie B. A. de Beer;G. van der Zwan;C. Gooijer;J. Commandeur;N. Vermeulen;C. Oostenbrink
三种新发现的细胞色素P450 BM 3的药物代谢突变体（货车Vugt‐Lussenburg et al.，使用随机诱变鉴定细胞色素P450 BM 3的新型药物代谢突变体中的关键残基，J Med Chem 2007;50：455-461）已经在原子水平上进行了研究，以提供其许多特征的结构解释。在这项研究中，计算方法与实验技术相结合。进行了分子动力学模拟、共振拉曼和紫外-可见光谱、耦合效率和底物结合实验。由实验结果支持的计算结果，使突变体的结构合理化。已知本研究中使用的底物通过人细胞色素P450 2D 6代谢。有趣的是，由P450 BM 3突变体形成的主要代谢产物与由人细胞色素P450 2D 6形成的代谢产物不同。计算结果，共振拉曼数据的支持下，建议的血红素丙酸基团之一的构象变化。建模结果进一步表明，这种构象变化允许血红素取代基的带负电荷的羧酸盐和带正电荷的氮的底物之间的相互作用。这使得底物的方向有利于P450 BM 3形成主要代谢产物。Proteins 2008.© 2007 Wiley利斯公司
Three newly discovered drug metabolizing mutants of cytochrome P450 BM3 (van Vugt‐Lussenburg et al., Identification of critical residues in novel drug metabolizing mutants of Cytochrome P450 BM3 using random mutagenesis, J Med Chem 2007;50:455–461) have been studied at an atomistic level to provide structural explanations for a number of their characteristics. In this study, computational methods are combined with experimental techniques. Molecular dynamics simulations, resonance Raman and UV–VIS spectroscopy, as well as coupling efficiency and substrate‐binding experiments, have been performed. The computational findings, supported by the experimental results, enable structural rationalizations of the mutants. The substrates used in this study are known to be metabolized by human cytochrome P450 2D6. Interestingly, the major metabolites formed by the P450 BM3 mutants differ from those formed by human cytochrome P450 2D6. The computational findings, supported by resonance Raman data, suggest a conformational change of one of the heme propionate groups. The modeling results furthermore suggest that this conformational change allows for an interaction between the negatively charged carboxylate of the heme substituent and the positively charged nitrogen of the substrates. This allows for an orientation of the substrates favorable for formation of the major metabolite by P450 BM3. Proteins 2008. © 2007 Wiley‐Liss, Inc.
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影响因子：
56.9
作者：
RAVICHANDRAN, KG;BODDUPALLI, SS;DEISENHOFER, J
通讯作者：
DEISENHOFER, J
影响因子：
3.9
作者：
BODDUPALLI, SS;PRAMANIK, BC;PETERSON, JA
通讯作者：
PETERSON, JA
影响因子：
3.9
作者：
Reed, JR;Hollenberg, PF
通讯作者：
Hollenberg, PF
DOI：
10.1073/pnas.96.5.1863
发表时间：
1999-03-02
影响因子：
11.1
作者：
Sevrioukova, IF;Li, HY;Poulos, TL
通讯作者：
Poulos, TL
影响因子：
2.9
作者：
Haines, DC;Tomchick, DR;Peterson, JA
通讯作者：
Peterson, JA