Pandda Analysis Of Nudt7 Screened Against Dspl And Oxxchem Fragment Libraries
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<strong>SGC Oxford has performed a crystallographic fragment screen on the human peroxisomal coenzyme A diphosphatase NUDT7 (UniProtKB - P0C024). All structures with clearly identifiable ligands were deposited in the Protein Data Bank under Group Deposition ID G_1002045. The final structures and the relevant PanDDA event maps can be found at the SGC fragment screening website. This work is part of the Target Enabling Package (TEP) program at SGC and the complete TEP for NUDT7 is will also be available on ZENODO shortly.</strong> <em><strong>Experiment</strong></em> Crystals were prepared at the XChem facility of the Diamond Light Source (DLS). Briefly, crystals were soaked overnight with two fragment libraries; the Diamond- SGC Poised Library set (Cox et al., 2016) and the OxXChem set with nominal fragment concentrations of 100 mM, with DMSO at 30% v/v. Additionally, a series of follow-up compounds based on an initial fragment hit was synthesized and soaked overnight with nominal compound concentrations of 30 mM, with DMSO at 30% v/v. All datasets were collected at MX beamlines at DLS. Autoprocessed datasets were analysed by Pan-Dataset Density Analysis (PanDDA) (Pearce et al., 2017). All ligands that were clearly identifiable in PanDDA event maps were modelled, refined and deposited into the PDB. <em><strong>Content</strong></em> This repository contains: all results from the PanDDA analysis, including ground-state-mean maps and PanDDA event & Z-maps for all ligand bound structures MTZ and AIMLESS logfiles from auto-processing PDB, CIF & PNG files of all the soaked compounds final refine.pdb and refine.mtz filess of all ligand bound structures all data belonging to an individual crystal can be found in <em>processed_datasets/<crystal_ID></em> <em><strong>References</strong></em> Cox, O. B. et al. A poised fragment library enables rapid synthetic expansion yielding the first reported inhibitors of PHIP(2), an atypical bromodomain. Chem. Sci. 7, 2322–2330 (2016). Pearce, N. M. et al. A multi-crystal method for extracting obscured crystallographic states from conventionally uninterpretable electron density. Nat Commun 8, (2017).
结构基因组学联盟（Structural Genomics Consortium, SGC）牛津分部针对人类过氧化物酶体辅酶A二磷酸酶NUDT7（通用蛋白质资源知识库（Universal Protein Resource Knowledgebase, UniProtKB）编号：P0C024）开展了晶体学片段筛选实验。所有配体可明确识别的结构已以分组提交编号G_1002045入库至蛋白质数据银行（Protein Data Bank, PDB）。最终结构与相关PanDDA事件图可于SGC片段筛选网站获取。本研究为SGC靶点赋能套件（Target Enabling Package, TEP）项目的一部分，NUDT7的完整TEP内容也将于近期在ZENODO平台发布。 ## 实验 实验所用晶体均在钻石光源（Diamond Light Source, DLS）的XChem平台制备。简要而言，晶体分别经两种片段文库过夜浸泡：分别为Diamond-SGC预设片段文库（Cox等，2016）与OxXChem文库，片段终浓度标称值为100 mM，二甲基亚砜（Dimethyl Sulfoxide, DMSO）体积占比为30%。此外，研究团队基于初始片段命中化合物合成了一系列衍生化合物，并以标称浓度30 mM、DMSO体积占比30%的体系过夜浸泡晶体。所有衍射数据均采集自DLS的MX光束线站。经自动处理的衍射数据集通过数据集密度全景分析（PanDDA）方法进行分析（Pearce等，2017）。所有在PanDDA事件图中可明确识别的配体均经过建模、精修后提交至PDB。 ## 数据集内容 本数据集仓库包含以下内容： - 所有PanDDA分析结果，包括所有配体结合结构的基态平均图、PanDDA事件图与Z图； - 自动处理流程生成的MTZ格式文件与AIMLESS日志文件； - 所有浸泡实验所用化合物的PDB、CIF及PNG格式文件； - 所有配体结合结构的最终精修文件refine.pdb与refine.mtz； - 单颗晶体的所有相关数据均可在`processed_datasets/<crystal_ID>`路径下获取。 ## 参考文献 [1] Cox, O. B. 等. 预设片段文库支持快速合成衍生，获得首个非典型溴结构域PHIP(2)抑制剂[J]. 化学科学, 2016, 7: 2322-2330. [2] Pearce, N. M. 等. 从常规难以解析的电子密度中提取隐藏晶体状态的多晶体分析方法[J]. 自然通讯, 2017, 8.
