Vankadari Naveen
Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia.
J Phys Chem Lett. 2020 Aug 20;11(16):6655-6663. doi: 10.1021/acs.jpclett.0c01698. Epub 2020 Aug 5.
The COVID-19 pandemic is an urgent global health emergency, and the presence of Furin site in the SARS-CoV-2 spike glycoprotein alters virulence and warrants further molecular, structural, and biophysical studies. Here we report the structure of Furin in complex with SARS-CoV-2 spike glycoprotein, demonstrating how Furin binds to the S1/S2 region of spike glycoprotein and eventually cleaves the viral protein using experimental functional studies, molecular dynamics, and docking. The structural studies underline the mechanism and mode of action of Furin, which is a key process in host cell entry and a hallmark of enhanced virulence. Our whole-exome sequencing analysis shows the genetic variants/alleles in Furin were found to alter the binding affinity for viral spike glycoprotein and could vary in infectivity in humans. Unravelling the mechanisms of Furin action, binding dynamics, and the genetic variants opens the growing arena of bona fide antibodies and development of potential therapeutics targeting the blockage of Furin cleavage.
新冠疫情是一场紧迫的全球卫生突发事件，而严重急性呼吸综合征冠状病毒2（SARS-CoV-2）刺突糖蛋白中弗林蛋白酶切割位点的存在改变了病毒毒力，因此有必要开展进一步的分子、结构和生物物理研究。在此，我们报告了弗林蛋白酶与SARS-CoV-2刺突糖蛋白复合物的结构，通过实验功能研究、分子动力学和对接，展示了弗林蛋白酶如何与刺突糖蛋白的S1/S2区域结合，并最终切割病毒蛋白。结构研究强调了弗林蛋白酶的作用机制和作用方式，这是宿主细胞进入过程中的关键步骤，也是病毒毒力增强的标志。我们的全外显子组测序分析表明，弗林蛋白酶中的基因变异/等位基因会改变其对病毒刺突糖蛋白的结合亲和力，并且在人类中的感染性可能有所不同。阐明弗林蛋白酶的作用机制、结合动力学以及基因变异，为真正的抗体和靶向阻断弗林蛋白酶切割的潜在疗法的开发开辟了广阔领域。
