Expedited mapping of the ligandable proteome using fully functionalized enantiomeric probe pairs
Expedited mapping of the ligandable proteome using fully functionalized enantiomeric probe pairs
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DOI：
10.1038/s41557-019-0351-5
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发表时间：
2019-12-01
期刊：
影响因子：
21.8
通讯作者：
Cravatt, Benjamin F.
中科院分区：
文献类型：
--
作者：
Wang, Yujia;Dix, Melissa M.;Cravatt, Benjamin F.
化学生物学和医学中的一个根本挑战是理解和扩大可以被小分子靶向的人类蛋白质组的部分。我们最近描述了一种将基于片段的配体发现与化学蛋白质组学相结合的策略，以提供人类细胞中可逆的小分子/蛋白质相互作用的全球肖像。然而，从这些“配位性”图谱中挖掘清晰的结构-活性关系，被个别片段的不同物理化学性质和相应的整体蛋白质结合潜力所混淆。在这里，我们描述了一个令人信服的解决方案，通过引入一组仅在绝对立体化学上不同的下一代完全功能化的片段。使用这些对映体探针对，我们确定了细胞中大量立体选择性的蛋白质-片段相互作用，并表明这些相互作用发生在不同类别蛋白质的功能位点上。因此，我们的发现表明，将手性结合到完全功能化的片段库中提供了一种稳健和简化的方法来发现细胞中的可连接蛋白。
A fundamental challenge in chemical biology and medicine is to understand and expand the fraction of the human proteome that can be targeted by small molecules. We recently described a strategy that integrates fragment-based ligand discovery with chemical proteomics to furnish global portraits of reversible small-molecule/protein interactions in human cells. Excavating clear structure-activity relationships from these 'ligandability' maps, however, was confounded by the distinct physicochemical properties and corresponding overall protein-binding potential of individual fragments. Here, we describe a compelling solution to this problem by introducing a next-generation set of fully functionalized fragments differing only in absolute stereochemistry. Using these enantiomeric probe pairs, or 'enantioprobes', we identify numerous stereoselective protein-fragment interactions in cells and show that these interactions occur at functional sites on proteins from diverse classes. Our findings thus indicate that incorporating chirality into fully functionalized fragment libraries provides a robust and streamlined method to discover ligandable proteins in cells.