Crystal polymorphism in fragment-based lead discovery of ligands of the catalytic domain of UGGT, the glycoprotein folding quality control checkpoint.
Crystal polymorphism in fragment-based lead discovery of ligands of the catalytic domain of UGGT, the glycoprotein folding quality control checkpoint.
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DOI：
10.3389/fmolb.2022.960248
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发表时间：
2022
影响因子：
5
通讯作者：
中科院分区：
文献类型：
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用于基于X射线晶体学碎片的铅发现（FBLD）的当前数据处理流水线中没有一个在决定晶格和对称性（即，多晶型物）。通常，X射线晶体学FBLD管道要么基于X射线衍射数据的单元体积和点群对称性选择多晶型物，要么将多晶型物归因于用户的手动干预。因此，当FBLD晶体属于多于一种晶体多晶型物时，发现管道可能受到空间群模糊性的困扰，特别是如果手头的多晶型物是相同晶格的变体，并且因此难以区分它们的形态和/或它们的表观晶格和点群。在一个片段为基础的铅发现努力的过程中，旨在寻找UDP-葡萄糖蛋白葡萄糖基转移酶（UGGT）的催化结构域的配体，我们遇到了三角晶体和pseudotrigonal三斜晶体的混合物与两个晶格密切相关。为了解决多态性的模糊性，我们在这里编写并描述了一系列Unix shell脚本，称为CoALLA（基于晶体多晶型和配体可能性的分配）。CoALLA脚本在Unix shell中编写，使用autoPROC进行数据处理，使用CCP 4-Dimple/REFMAC 5和BUSTER进行优化，使用RHOFIT进行配体对接。多晶型物的选择通过进行（在每种已知的多晶型物中）衍射数据索引、积分、缩放和结构细化的任务来实现。然后选择最有可能的多晶型物作为具有最佳结构细化Rfree统计的多晶型物。CoALLA脚本进一步实施基于可能性的配体分配策略，从大分子细化和自动化水添加开始，然后去除看起来适合配体密度的水分子，并在细化的大分子模型的随机扰动后进行最后一轮细化，以获得用于自动化配体放置的无偏差异密度图。我们说明了使用CoALLA区分H3和P1晶体用于FBLD努力找到片段结合到催化结构域的嗜热毛壳菌UGGT。
None of the current data processing pipelines for X-ray crystallography fragment-based lead discovery (FBLD) consults all the information available when deciding on the lattice and symmetry (i.e., the polymorph) of each soaked crystal. Often, X-ray crystallography FBLD pipelines either choose the polymorph based on cell volume and point-group symmetry of the X-ray diffraction data or leave polymorph attribution to manual intervention on the part of the user. Thus, when the FBLD crystals belong to more than one crystal polymorph, the discovery pipeline can be plagued by space group ambiguity, especially if the polymorphs at hand are variations of the same lattice and, therefore, difficult to tell apart from their morphology and/or their apparent crystal lattices and point groups. In the course of a fragment-based lead discovery effort aimed at finding ligands of the catalytic domain of UDP–glucose glycoprotein glucosyltransferase (UGGT), we encountered a mixture of trigonal crystals and pseudotrigonal triclinic crystals—with the two lattices closely related. In order to resolve that polymorphism ambiguity, we have written and described here a series of Unix shell scripts called CoALLA (crystal polymorph and ligand likelihood-based assignment). The CoALLA scripts are written in Unix shell and use autoPROC for data processing, CCP4-Dimple/REFMAC5 and BUSTER for refinement, and RHOFIT for ligand docking. The choice of the polymorph is effected by carrying out (in each of the known polymorphs) the tasks of diffraction data indexing, integration, scaling, and structural refinement. The most likely polymorph is then chosen as the one with the best structure refinement Rfree statistic. The CoALLA scripts further implement a likelihood-based ligand assignment strategy, starting with macromolecular refinement and automated water addition, followed by removal of the water molecules that appear to be fitting ligand density, and a final round of refinement after random perturbation of the refined macromolecular model, in order to obtain unbiased difference density maps for automated ligand placement. We illustrate the use of CoALLA to discriminate between H3 and P1 crystals used for an FBLD effort to find fragments binding to the catalytic domain of Chaetomium thermophilum UGGT.
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DOI：
10.1107/s090744491003982x
发表时间：
2011-04
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Evans PR
通讯作者：
Evans PR
DOI：
10.1107/s2053230x1500967x
发表时间：
2015-07
期刊：
Acta crystallographica. Section F, Structural biology communications
影响因子：
--
作者：
Gorrec F
通讯作者：
Gorrec F
集成到基于片段的先导化合物发现流程中的配体观察质谱方法
影响因子：
4.6
作者：
Chen X;Qin S;Chen S;Li J;Li L;Wang Z;Wang Q;Lin J;Yang C;Shui W
通讯作者：
Shui W
影响因子：
1.2
作者：
Douangamath, Alice;Powell, Ailsa;von Delft, Frank
通讯作者：
von Delft, Frank
DOI：
10.1107/s0907444904016427
发表时间：
2004-12-01
影响因子：
2.2
作者：
Blanc, E;Roversi, P;Bricogne, G
通讯作者：
Bricogne, G