Homology model of human retinoic acid metabolising enzyme cytochrome P450 26A1 (CYP26A1): Active site architecture and ligand binding
Homology model of human retinoic acid metabolising enzyme cytochrome P450 26A1 (CYP26A1): Active site architecture and ligand binding
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DOI：
10.1080/14756360600742014
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发表时间：
2006-08-01
影响因子：
5.6
通讯作者：
Brancale, Andrea
中科院分区：
文献类型：
--
作者：
Gomaa, Mohamed Sayed;Yee, Sook Wah;Brancale, Andrea
以人细胞色素P450的3种结构（CYP 2C 8、CYP 2C 9和CYP 3A 4）为模板，构建了细胞色素P450 RA 1（CYP 26 A1）的同源性模型。然后使用莫伊软件评估最低能量CYP 26 A1模型的立体化学质量和侧链环境。通过分子动力学对使用CYP 3A 4模板构建的CYP 26 A1模型进行进一步活性位点优化，以生成最终CYP 26 A1模型。天然底物，全反式维甲酸（atRA），和抑制剂R115866，对接到模型中，允许进一步验证的活性位点架构。使用对接研究，结构和功能上重要的残基进行了鉴定，随后的二级结构表征。多种疏水相互作用，包括TRP 112、PHE 299、PHE 222、PHE 84、PHE 374和PRO371的侧链，对于atRA和R115866的结合是重要的。另外的氢键相互作用记录如下：atRA-atRA羧酸酯基团的C=O和ARG 86; R115866苯并噻唑氮和SER 115的骨架NH。
Homology models of cytochrome P450 RA1 (CYP26A1) were constructed using three human P450 structures, CYP2C8, CYP2C9 and CYP3A4 as templates for the model building. Using MOE software the lowest energy CYP26A1 model was then assessed for stereochemical quality and side chain environment. Further active site optimisation of the CYP26A1 model built using the CYP3A4 template was performed by molecular dynamics to generate a final CYP26A1 model. The natural substrate, all-trans-retinoic acid (atRA), and inhibitor R115866, were docked into the model allowing further validation of the active site architecture. Using the docking studies structurally and functionally important residues were identified with subsequent characterisation of secondary structure. Multiple hydrophobic interactions, including the side chains of TRP112, PHE299, PHE222, PHE84, PHE374 and PRO371, are important for binding of atRA and R115866. Additional hydrogen bonding interactions were noted as follows: atRA - C=O of the atRA carboxylate group and ARG86; R115866 benzothiazole nitrogen and the backbone NH of SER115.