Conformational Selection in Ligand Recognition by the First Tudor Domain of PHF20L1
Conformational Selection in Ligand Recognition by the First Tudor Domain of PHF20L1
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PHF20L1 第一个 Tudor 结构域在配体识别中的构象选择
DOI：
10.1021/acs.jpclett.0c02039
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发表时间：
2020-09-17
影响因子：
5.7
通讯作者：
Ruan, Ke
中科院分区：
文献类型：
--
作者：
Lv, Mengqi;Gao, Jia;Ruan, Ke
PHF20L1的第一个都铎结构域（Tudor1）识别（非）组蛋白甲基化，发挥多种作用。然而，潜在的配体识别机制仍然是未知的，因为在自由形式结构中揭示了一个封闭状态。核磁共振弛豫色散和分子动力学模拟表明，PHF20L1 Tudor1的芳香族笼型残基存在显著重排的低居群构象。这种开放式构象被用来识别赖氨酸142甲基化DNMT1、助溶剂和核磁共振片段筛选击中，如复杂的晶体结构所揭示的那样。有趣的是，配体结合能力仅通过调整开放状态种群的突变而增强。在癌细胞中进一步验证了PHF20L1对DNMT1的识别。这种构象选择机制将有助于发现针对看似“不可药物”的PHF20L1 Tudor1的小分子抑制剂。
The first Tudor domain (Tudor1) of PHF20L1 recognizes (non)histone methylation to play versatile roles. However, the underlying ligand-recognition mechanism remains unknown as a closed state revealed in the free-form structure. NMR relaxation dispersion and molecular dynamics simulations suggest a pre-existing low-population conformation with a remarkable rearrangement of aromatic cage residues of PHF20L1 Tudor1. Such an open-form conformation is utilized to recognize lysine 142 methylated DNMT1, a cosolvent, and an NMR fragment screening hit, as revealed by the complex crystal structures. Intriguingly, the ligand binding capacity was enhanced by mutation that tunes up the open-state population only. The recognition of DNMT1 by PHF20L1 was further validated in cancer cells. This conformational selection mechanism will enable the discovery of small molecule inhibitors against the seemingly "undruggable" PHF20L1 Tudor1.