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首页> 美国卫生研究院文献>Antimicrobial Agents and Chemotherapy >Three-Dimensional Models of Wild-Type and Mutated Forms of Cytochrome P450 14α-Sterol Demethylases from Aspergillus fumigatus and Candida albicans Provide Insights into Posaconazole Binding
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Three-Dimensional Models of Wild-Type and Mutated Forms of Cytochrome P450 14α-Sterol Demethylases from Aspergillus fumigatus and Candida albicans Provide Insights into Posaconazole Binding

机译：烟曲霉和白色念珠菌的细胞色素P45014α-甾醇脱甲基酶的野生型和突变形式的三维模型提供了对泊沙康唑结合的见解

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摘要

The cytochrome P450 sterol 14α-demethylase enzyme (CYP51) is the target of azole antifungals. Azoles block ergosterol synthesis, and thereby fungal growth, by binding in the active-site cavity of the enzyme and ligating the iron atom of the heme cofactor through a nitrogen atom of the azole. Mutations in and around the CYP51 active site have resulted in azole resistance. In this work, homology models of the CYP51 enzymes from Aspergillus fumigatus and Candida albicans were constructed based on the X-ray crystal structure of CYP51 from Mycobacterium tuberculosis. Using these models, binding modes for voriconazole (VOR), fluconazole (FLZ), itraconazole (ITZ), and posaconazole (POS) were predicted from docking calculations. Previous work had demonstrated that mutations in the vicinity of the heme cofactor had a greater impact on the binding of FLZ and VOR than on the binding of POS and ITZ. Our modeling data suggest that the long side chains of POS and ITZ occupy a specific channel within CYP51 and that this additional interaction, which is not available to VOR and FLZ, serves to stabilize the binding of these azoles to the mutated CYP51 proteins. The model also predicts that mutations that were previously shown to specifically impact POS susceptibility in A. fumigatus and C. albicans act by interfering with the binding of the long side chain.
机译：细胞色素P450甾醇14α-脱甲基酶（CYP51）是唑类抗真菌药的目标。偶氮化合物通过结合在酶的活性部位腔中并通过唑的氮原子连接血红素辅因子的铁原子来阻断麦角固醇的合成，从而阻止真菌的生长。 CYP51活性位点及其周围的突变导致对唑的抗性。在这项工作中，基于来自结核分枝杆菌的CYP51的X射线晶体结构，构建了来自烟曲霉和白色念珠菌的CYP51酶的同源性模型。使用这些模型，通过对接计算预测了伏立康唑（VOR），氟康唑（FLZ），伊曲康唑（ITZ）和泊沙康唑（POS）的结合模式。先前的研究表明，血红素辅因子附近的突变对FLZ和VOR的结合比对POS和ITZ的结合具有更大的影响。我们的建模数据表明POS和ITZ的长侧链占据了CYP51内的特定通道，并且这种额外的相互作用（对于VOR和FLZ不可用）起到稳定这些唑与突变的CYP51蛋白结合的作用。该模型还预测，以前显示出可特异性影响烟曲霉和白色念珠菌中POS敏感性的突变会通过干扰长侧链的结合而起作用。

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