Theoretical investigation of substrate specificity for cytochromes p450 IA2, p450 IID6 and p450 IIIA4
Theoretical investigation of substrate specificity for cytochromes p450 IA2, p450 IID6 and p450 IIIA4
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DOI：
10.1023/a:1008187802746
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发表时间：
2000-01-01
影响因子：
3.5
通讯作者：
De Benedetti, PG
中科院分区：
文献类型：
--
作者：
De Rienzo, F;Fanelli, F;De Benedetti, PG
以细胞色素P450 CAM、P450 BM-3、P450 TERP和P450 ERYF的X射线晶体结构为模板，通过比较建模的方法建立了细胞色素P450 IA2、P450 IID6和P450 IIIA4的三维模型。分析了这三种细胞色素的内在结构特征以及它们与50种特异性和非特异性底物的相互作用性质。通过自动刚性对接和柔性对接获得底物/酶复合体。通过对三种细胞色素和所选底物的游离态和结合态的比较分析，可以根据分子和分子间相互作用描述符建立底物专一性的半定量模型。本研究结果为三种不同的真核细胞P450同工酶底物专一性的分子决定因素提供了新的见解，并为预测新化合物的专一性提供了有用的工具。
Three-dimensional models of the cytochromes P450 IA2, P450 IID6 and P450 IIIA4 were built by means of comparative modeling using the X-ray crystallographic structures of P450 CAM, P450 BM-3, P450 TERP and P450 ERYF as templates. The three cytochromes were analyzed both in their intrinsic structural features and in their interaction properties with fifty specific and non-specific substrates. Substrate/enzyme complexes were obtained by means of both automated rigid and flexible body docking. The comparative analysis of the three cytochromes and the selected substrates, in their free and bound forms, allowed for the building of semi-quantitative models of substrate specificity based on both molecular and intermolecular interaction descriptors. The results of this study provide new insights into the molecular determinants of substrate specificity for the three different eukaryotic P450 isozymes and constitute a useful tool for predicting the specificity of new compounds.