发现小分子激活酯酶 D 的机制。
Finding the mechanism of esterase D activation by a small molecule.
机构信息
Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Qingdao 266237, PR China; Hubei Key Laboratory of Edible Wild Plants Conservation & Utilization, National Demonstration Center for Experimental Biology Education, School of Life Science, Hubei Normal University, Huangshi 435002, PR China.
Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Qingdao 266237, PR China.
出版信息
Bioorg Med Chem Lett. 2020 Jun 1;30(11):127150. doi: 10.1016/j.bmcl.2020.127150. Epub 2020 Mar 29.
People with reduced esterase D (ESD) activity are susceptible to many diseases. However, how to activate ESD is still unknown. To address the question, we identified that 4-chloro-2-(5-phenyl-1-(pyridin-2-yl)-4, 5-dihydro-1H-pyrazol-3-yl) phenol (FPD5) could be a good candidate activator for ESD activity. We found that FPD5 could increase ESD activity in a dose-dependent way. FPD5 bound directly to ESD at Lys180 rather than its ubiquitination site Lys213. Site-directed mutagenesis at the binding site or the ubiquitination site inhibited FPD5 action. FPD5 increased the level of ESD mono-ubiquitination and mutESD K213A completely inhibited this action. Our findings highlighted the activation mechanism of ESD via promoting the mono-ubiquitination of ESD.
酯酶 D（ESD）活性降低的人容易患上许多疾病。然而，如何激活 ESD 仍然未知。为了解决这个问题，我们发现 4-氯-2-（5-苯基-1-（2-吡啶基）-4,5-二氢-1H-吡唑-3-基）苯酚（FPD5）可能是激活 ESD 活性的一个很好的候选物。我们发现 FPD5 可以以剂量依赖的方式增加 ESD 活性。FPD5 直接结合到 ESD 的 Lys180 上，而不是其泛素化位点 Lys213。结合位点或泛素化位点的定点突变抑制了 FPD5 的作用。FPD5 增加了 ESD 的单泛素化水平，而 mutESD K213A 完全抑制了这种作用。我们的发现强调了通过促进 ESD 的单泛素化来激活 ESD 的机制。
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