Optimizing the refinement of merohedrally twinned P61 HIV-1 protease-inhibitor cocrystal structures.
Optimizing the refinement of merohedrally twinned P61 HIV-1 protease-inhibitor cocrystal structures.
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优化细化单面孪晶 P61 HIV-1 蛋白酶抑制剂共晶结构。
DOI：
10.1107/s2059798320001989
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Schiffer,CeliaA
中科院分区：
文献类型：
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作者：
Lockbaum,GordonJ;Leidner,Florian;Royer,WilliamE;KurtYilmaz,Nese;Schiffer,CeliaA
孪生是一种晶体生长异常现象，其中蛋白质单体以不同方向存在，但以特定方式相关，导致衍射反射重叠。孪生对数据施加了额外的对称性，通常会导致分配更高的对称性空间群。具体来说，在多面体孪晶中，每个单体的反射重叠，需要孪生定律来对重叠反射的独特结构数据进行建模。在准旋转对称同源寡聚蛋白质结构的晶体学分析中忽略孪生可能会掩盖单体之间结构不一致的程度。特别是，如果在晶体学分析期间应用高于适当的对称性，则任何与完美对称性的偏差都将消失。这种情况需要在可能的最高对称性空间群之间进行选择，或者确定单体是否具有可区分的结构不对称性，从而需要较低的对称性空间群和孪生定律。使用 HIV-1 蛋白酶（一种 C2 对称同二聚体，其对称性被结合配体打破）的六角共晶体表明，指定较低对称性空间群和在精炼过程中应用孪生定律对于实现更准确地拟合电子密度的结构模型至关重要。通过重新分析最近发表的三种 HIV-1 蛋白酶结构，几乎所有晶体学指标都得到了改进。最重要的是，演示了一种可以在单一方向上可靠地对抑制剂进行建模的程序。该协议可能适用于 PDB 中的许多其他同源低聚物。
Twinning is a crystal-growth anomaly in which protein monomers exist in different orientations but are related in a specific way, causing diffraction reflections to overlap. Twinning imposes additional symmetry on the data, often leading to the assignment of a higher symmetry space group. Specifically, in merohedral twinning, reflections from each monomer overlap and require a twin law to model unique structural data from overlapping reflections. Neglecting twinning in the crystallographic analysis of quasi-rotationally symmetric homo-oligomeric protein structures can mask the degree of structural non-identity between monomers. In particular, any deviations from perfect symmetry will be lost if higher than appropriate symmetry is applied during crystallographic analysis. Such cases warrant choosing between the highest symmetry space group possible or determining whether the monomers have distinguishable structural asymmetries and thus require a lower symmetry space group and a twin law. Using hexagonal cocrystals of HIV-1 protease, a C2-symmetric homodimer whose symmetry is broken by bound ligand, it is shown that both assigning a lower symmetry space group and applying a twin law during refinement are critical to achieving a structural model that more accurately fits the electron density. By re-analyzing three recently published HIV-1 protease structures, improvements in nearly every crystallographic metric are demonstrated. Most importantly, a procedure is demonstrated where the inhibitor can be reliably modeled in a single orientation. This protocol may be applicable to many other homo-oligomers in the PDB.