SARS-CoV-2 3CLpro 对 NEMO 的切割的结构和功能特征。
Structural and functional characterization of NEMO cleavage by SARS-CoV-2 3CLpro.
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
Nat Commun. 2022 Sep 8;13(1):5285. doi: 10.1038/s41467-022-32922-9.
In addition to its essential role in viral polyprotein processing, the SARS-CoV-2 3C-like protease (3CLpro) can cleave human immune signaling proteins, like NF-κB Essential Modulator (NEMO) and deregulate the host immune response. Here, in vitro assays show that SARS-CoV-2 3CLpro cleaves NEMO with fine-tuned efficiency. Analysis of the 2.50 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.
除了在病毒多蛋白加工中的重要作用外，SARS-CoV-2 的 3C 样蛋白酶（3CLpro）还可以切割人类免疫信号蛋白，如 NF-κB 必需调节剂（NEMO），并使宿主免疫反应失调。在这里，体外测定表明，SARS-CoV-2 3CLpro 以精细的效率切割 NEMO。对 2.50 Å 分辨率的 3CLpro C145S 与 NEMO 结合的晶体结构的分析揭示了通过主链氢键容忍一系列病毒和宿主底物的亚基位，同时通过侧链氢键和疏水接触来强制特异性。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。我们假设 NEMO 的切割是 COVID-19 病理学中需要考虑的重要信息。
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