Beckman Institute, California Institute of Technology, Pasadena, CA 91125.
Proc Natl Acad Sci U S A. 2024 May 14;121(20):e2402653121. doi: 10.1073/pnas.2402653121. Epub 2024 May 9.
The intrinsically disordered C-terminal peptide region of severe acute respiratory syndrome coronavirus 2 nonstructural protein-1 (Nsp1-CT) inhibits host protein synthesis by blocking messenger RNA (mRNA) access to the 40S ribosome entrance tunnel. Aqueous copper(II) ions bind to the disordered peptide with micromolar affinity, creating a possible strategy to restore protein synthesis during host infection. Electron paramagnetic resonance (EPR) and tryptophan fluorescence measurements on a 10-residue model of the disordered protein region (Nsp1-CT), combined with advanced quantum mechanics calculations, suggest that the peptide binds to copper(II) as a multidentate ligand. Two optimized computational models of the copper(II)-peptide complexes were derived: One corresponding to pH 6.5 and the other describing the complex at pH 7.5 to 8.5. Simulated EPR spectra based on the calculated model structures are in good agreement with experimental spectra.
严重急性呼吸综合征冠状病毒 2 非结构蛋白-1（Nsp1-CT）的无规则 C 端肽区域通过阻止信使 RNA（mRNA）进入 40S 核糖体入口隧道来抑制宿主蛋白合成。水合铜（II）离子以微摩尔亲和力与无规则肽结合，为宿主感染期间恢复蛋白质合成创造了一种可能的策略。对无序蛋白区域（Nsp1-CT）的 10 残基模型进行电子顺磁共振（EPR）和色氨酸荧光测量，并结合先进的量子力学计算，表明该肽作为多齿配体与铜（II）结合。得出了两个优化的铜（II）-肽复合物计算模型：一个对应于 pH 6.5，另一个描述 pH 7.5 至 8.5 时的复合物。基于计算模型结构模拟的 EPR 光谱与实验光谱吻合良好。
