SARS-CoV-2 Omicron Variant Spike Glycoprotein Mutation Q954H Enhances Fusion Core Stability.

IF 3.5 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Nisansala Vithanage, Rifat Hasan Apurba, Hamza Enesi Ozomarisi, Carson J Bair, Eve L Sugg, Victor K Outlaw
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引用次数: 0

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant-of-concern has rapidly spread across the globe to become the dominant form of COVID-19 infection. The Omicron Spike (S) glycoprotein, which mediates viral entry into cells, possesses up to 34 mutations that contribute to the variant's increased transmissibility and decreased susceptibility to antibody-mediated immunity from vaccines or prior infections. One of those mutations, Q954H, occurs within the N-terminal heptad repeat (HR1) domain. During viral entry, the HR1 domain coassembles with the C-terminal heptad repeat (HR2) domain to form a stable six-helix bundle or "fusion core" structure, which brings the viral envelope and host membrane into proximity and thermodynamically drives membrane fusion. Here, we demonstrate that the Q954H mutation enhances the interaction between the HR1 and HR2 domains, thereby stabilizing the fusion core assembly relative to prior variants. We also report the first X-ray crystal structure of the Omicron S fusion core, which reveals that the Q954H side chain forms a N···H-O hydrogen bond with the side chain hydroxyl of S1175 within the HR2 domain, as well as an unexpected C-H···O hydrogen bonding interaction with the backbone carbonyl of N1173. Co-assembly with a synthetic depsipeptide, in which the amide of N1173 is replaced with an ester, results in a decreased assembly stability, providing evidence to support the importance of the observed hydrogen bond network. These insights will be valuable for analyzing the factors that drive viral evolution and for the development of inhibitors of SARS-CoV-2 entry.

SARS-CoV-2组微粒变异穗状糖蛋白突变Q954H增强融合核心稳定性
严重急性呼吸系统综合征冠状病毒2 (SARS-CoV-2) Omicron变种已迅速在全球蔓延,成为COVID-19感染的主要形式。介导病毒进入细胞的Omicron Spike (S)糖蛋白拥有多达34个突变,这些突变导致该变体的传播性增加,并降低了对疫苗或先前感染的抗体介导免疫的易感性。其中一个突变,Q954H,发生在n端七磷酸重复(HR1)结构域内。在病毒进入过程中,HR1结构域与c -末端七tad重复序列(HR2)结构域结合形成稳定的六螺旋束或“融合核”结构,使病毒包膜和宿主膜接近,并从热力学上驱动膜融合。在这里,我们证明了Q954H突变增强了HR1和HR2结构域之间的相互作用,从而相对于先前的变异稳定了融合核心组装。我们还报道了Omicron S核聚变核的第一个x射线晶体结构,揭示了Q954H侧链与S1175侧链羟基在HR2结构域内形成了N··h·O氢键,并与N1173的主羰基形成了意想不到的C-H··O氢键相互作用。与合成的沉积肽共组装,其中N1173的酰胺被酯取代,导致组装稳定性下降,为支持观察到的氢键网络的重要性提供了证据。这些见解对于分析驱动病毒进化的因素和开发SARS-CoV-2进入抑制剂将具有价值。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
ACS Chemical Biology
ACS Chemical Biology 生物-生化与分子生物学
CiteScore
7.50
自引率
5.00%
发文量
353
审稿时长
3.3 months
期刊介绍: ACS Chemical Biology provides an international forum for the rapid communication of research that broadly embraces the interface between chemistry and biology. The journal also serves as a forum to facilitate the communication between biologists and chemists that will translate into new research opportunities and discoveries. Results will be published in which molecular reasoning has been used to probe questions through in vitro investigations, cell biological methods, or organismic studies. We welcome mechanistic studies on proteins, nucleic acids, sugars, lipids, and nonbiological polymers. The journal serves a large scientific community, exploring cellular function from both chemical and biological perspectives. It is understood that submitted work is based upon original results and has not been published previously.
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