SARS-CoV-2 刺突蛋白的结构和突变：重点概述,ACS Infectious Diseases

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SARS-CoV-2 刺突蛋白的结构和突变：重点概述
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2021-12-02 , DOI: 10.1021/acsinfecdis.1c00433
Rukmankesh Mehra ₁ , Kasper P Kepp ₂

Affiliation

SARS-CoV-2的刺突蛋白（S蛋白）是病毒感染人类细胞的蛋白，是许多疫苗的基础，也是病毒进化的热点。在这里，我们讨论 S 蛋白结构表征方面的突出进展，以及这些结构如何促进病毒功能和进化的分析。我们强调报告结构的差异，并且结构-功能关系的分析对所使用的结构敏感。我们表明，几乎完整结构中的平均残留溶剂暴露是开放与封闭构象状态的良好描述。由于功能重要的表面暴露残基的结构异质性，我们建议在得出特定结构-功能关系的结论之前使用一组高质量蛋白质结构的平均值，而不是单个结构。为了说明这些观点，我们在现有结构的背景下分析了显着 S 蛋白突变的一些显着化学趋势。在讨论新变体时，我们强调与 ACE2 结合相对于主要抗体的选择性，而不是简单地分别单独地抗体逃逸或 ACE2 亲和力。我们注意到，较大的化学变化，特别是暴露表面残基的静电荷或侧链体积的增加，在所关注的突变中反复出现，这可能与适应人类 ACE2 的负表面电位有关。我们还发现有迹象表明，主要变体中 S 蛋白的固定突变比预期的平均不稳定程度要小，这可能表明 S 蛋白存在选择压力。适用于所有这些情况的丰富的可用结构为未来研究这些结构-功能关系提供了极其有价值的基础。

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Structure and Mutations of SARS-CoV-2 Spike Protein: A Focused Overview

The spike protein (S-protein) of SARS-CoV-2, the protein that enables the virus to infect human cells, is the basis for many vaccines and a hotspot of concerning virus evolution. Here, we discuss the outstanding progress in structural characterization of the S-protein and how these structures facilitate analysis of virus function and evolution. We emphasize the differences in reported structures and that analysis of structure–function relationships is sensitive to the structure used. We show that the average residue solvent exposure in nearly complete structures is a good descriptor of open vs closed conformation states. Because of structural heterogeneity of functionally important surface-exposed residues, we recommend using averages of a group of high-quality protein structures rather than a single structure before reaching conclusions on specific structure–function relationships. To illustrate these points, we analyze some significant chemical tendencies of prominent S-protein mutations in the context of the available structures. In the discussion of new variants, we emphasize the selectivity of binding to ACE2 vs prominent antibodies rather than simply the antibody escape or ACE2 affinity separately. We note that larger chemical changes, in particular increased electrostatic charge or side-chain volume of exposed surface residues, are recurring in mutations of concern, plausibly related to adaptation to the negative surface potential of human ACE2. We also find indications that the fixated mutations of the S-protein in the main variants are less destabilizing than would be expected on average, possibly pointing toward a selection pressure on the S-protein. The richness of available structures for all of these situations provides an enormously valuable basis for future research into these structure–function relationships.

更新日期：2022-01-14

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