Prokop Jeremy W, Alberta Sheryl, Witteveen-Lane Martin, Pell Samantha, Farag Hosam A, Bhargava Disha, Vaughan Robert M, Frisch Austin, Bauss Jacob, Bhatti Humza, Arora Sanjana, Subrahmanya Charitha, Pearson David, Goodyke Austin, Westgate Mason, Cook Taylor W, Mitchell Jackson T, Zieba Jacob, Sims Matthew D, Underwood Adam, Hassouna Habiba, Rajasekaran Surender, Tamae Kakazu Maximiliano A, Chesla Dave, Olivero Rosemary, Caulfield Adam J
Office of Research, Corewell Health, Grand Rapids, MI 49503, USA.
College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA.
Microorganisms. 2024 Sep 9;12(9):1863. doi: 10.3390/microorganisms12091863.
As of 2024, SARS-CoV-2 continues to propagate and drift as an endemic virus, impacting healthcare for years. The largest sequencing initiative for any species was initiated to combat the virus, tracking changes over time at a full virus base-pair resolution. The SARS-CoV-2 sequencing represents a unique opportunity to understand selective pressures and viral evolution but requires cross-disciplinary approaches from epidemiology to functional protein biology. Within this work, we integrate a two-year genotyping window with structural biology to explore the selective pressures of SARS-CoV-2 on protein insights. Although genotype and the Spike (Surface Glycoprotein) protein continue to drift, most SARS-CoV-2 proteins have had few amino acid alterations. Within Spike, the high drift rate of amino acids involved in antibody evasion also corresponds to changes within the ACE2 binding pocket that have undergone multiple changes that maintain functional binding. The genotyping suggests selective pressure for receptor specificity that could also confer changes in viral risk. Mapping of amino acid changes to the structures of the SARS-CoV-2 co-transcriptional complex (nsp7-nsp14), nsp3 (papain-like protease), and nsp5 (cysteine protease) proteins suggest they remain critical factors for drug development that will be sustainable, unlike those strategies targeting Spike.
截至2024年，严重急性呼吸综合征冠状病毒2（SARS-CoV-2）作为一种地方性病毒继续传播和变异，多年来一直影响着医疗保健。为对抗该病毒发起了针对任何物种的最大规模测序计划，以全病毒碱基对分辨率追踪随时间的变化。SARS-CoV-2测序为了解选择压力和病毒进化提供了独特机会，但需要从流行病学到功能蛋白质生物学的跨学科方法。在这项工作中，我们将两年的基因分型窗口与结构生物学相结合，以探索SARS-CoV-2对蛋白质见解的选择压力。尽管基因型和刺突（表面糖蛋白）蛋白继续变异，但大多数SARS-CoV-2蛋白的氨基酸变化很少。在刺突蛋白中，参与抗体逃避的氨基酸高变异率也对应于血管紧张素转换酶2（ACE2）结合口袋内的变化，该口袋经历了多次维持功能结合的变化。基因分型表明受体特异性存在选择压力，这也可能导致病毒风险的变化。将氨基酸变化映射到SARS-CoV-2共转录复合物（nsp7-nsp14）、nsp3（木瓜样蛋白酶）和nsp5（半胱氨酸蛋白酶）蛋白的结构上表明，它们仍然是药物开发的关键因素，与针对刺突蛋白的策略不同，这些因素将具有可持续性。
