SARS-CoV-2 3CL蛋白酶对NEMO的切割作用的结构与功能表征
Structural and functional characterization of NEMO cleavage by SARS-CoV-2 3CLpro.
作者信息
Hameedi Mikhail Ali, Prates Erica T, Garvin Michael R, Mathews Irimpan, Amos B Kirtley, Demerdash Omar, Bechthold Mark, Iyer Mamta, Rahighi Simin, Kneller Daniel W, Kovalevsky Andrey, Irle Stephan, Vuong Van-Quan, Mitchell Julie C, Labbe Audrey, Galanie Stephanie, Wakatsuki Soichi, Jacobson Daniel
机构信息
SLAC National Accelerator Laboratory, Stanford Synchrotron Radiation Lightsource, Structural Molecular Biology, Menlo Park, CA 94025, USA.
SLAC National Accelerator Laboratory, Stanford Synchrotron Radiation Lightsource, Biosciences, Menlo Park, CA 94025, USA.
出版信息
bioRxiv. 2021 Nov 15:2021.11.11.468228. doi: 10.1101/2021.11.11.468228.
In addition to its essential role in viral polyprotein processing, the SARS-CoV-2 3C-like (3CLpro) protease can cleave human immune signaling proteins, like NF-κB Essential Modulator (NEMO) and deregulate the host immune response. Here, assays show that SARS-CoV-2 3CLpro cleaves NEMO with fine-tuned efficiency. Analysis of the 2.14 Å resolution crystal structure of 3CLpro C145S bound to NEMO reveals subsites that tolerate a range of viral and host substrates through main chain hydrogen bonds while also enforcing specificity using side chain hydrogen bonds and hydrophobic contacts. Machine learning- and physics-based computational methods predict that variation in key binding residues of 3CLpro- NEMO helps explain the high fitness of SARS-CoV-2 in humans. We posit that cleavage of NEMO is an important piece of information to be accounted for in the pathology of COVID-19.
除了在病毒多聚蛋白加工中发挥关键作用外，严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的3C样（3CLpro）蛋白酶还可以切割人类免疫信号蛋白，如核因子κB关键调节因子（NEMO），并解除宿主免疫反应的调节。在此，实验表明SARS-CoV-2 3CLpro以微调的效率切割NEMO。对与NEMO结合的3CLpro C145S的2.14 Å分辨率晶体结构分析揭示了一些亚位点，这些亚位点通过主链氢键容忍一系列病毒和宿主底物，同时也利用侧链氢键和疏水接触来强化特异性。基于机器学习和物理的计算方法预测，3CLpro-NEMO关键结合残基的变异有助于解释SARS-CoV-2在人类中的高适应性。我们认为，NEMO的切割是新冠肺炎病理学中需要考虑的重要信息。
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