He Xiuxiu, Liu Huanzhen, Yang Guang, Yan Lei
School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing 210023, China.
Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China.
Viruses. 2025 Feb 28;17(3):343. doi: 10.3390/v17030343.
Human coronavirus OC43 (HCoV-OC43) is usually associated with common colds, but also related to severe disease in the frail. Its envelope glycoproteins spike (S) is responsible for host-cell attachment and membrane fusion. To understand the molecular basis of membrane fusion of HCoV-OC43, we solved the 3.34 Å crystal structure of the post-fusion state formed by two heptad repeat domains (HR1P and HR2P) of OC43-S. This fusion core comprises a parallel trimeric coiled coil of three HR1 helices with 61 Å at length, around which three HR2 helices are entwined in an antiparallel manner, as anticipated. Moreover, a pan-CoV fusion inhibitor EK1 derived from OC43-HR2P was also crystalized with OC43-HR1P in the resolution of 2.71 Å. Parallel comparisons rationalize the design of EK1, maintaining various hydrophobic and charged or hydrophilic interactions formed in the initial fusion core to stabilize the overall conformation. Together, our results not only reveal the critical intrahelical and interhelical interactions underlying the mechanism of action of OC43-S fusion, but also help our understanding on the mechanism of HCoV-OC43 inhibition by analogue HR2 mimic peptide.
人冠状病毒OC43（HCoV-OC43）通常与普通感冒相关，但也与体弱人群的严重疾病有关。其包膜糖蛋白刺突（S）负责宿主细胞的附着和膜融合。为了了解HCoV-OC43膜融合的分子基础，我们解析了由OC43-S的两个七肽重复结构域（HR1P和HR2P）形成的融合后状态的3.34 Å晶体结构。这个融合核心由三个HR1螺旋组成的平行三聚体卷曲螺旋构成，长度为61 Å，正如预期的那样，三个HR2螺旋以反平行方式缠绕在其周围。此外，源自OC43-HR2P的泛冠状病毒融合抑制剂EK1也与OC43-HR1P一起结晶，分辨率为2.71 Å。平行比较为EK1的设计提供了理论依据，维持了初始融合核心中形成的各种疏水、带电或亲水相互作用，以稳定整体构象。总之，我们的结果不仅揭示了OC43-S融合作用机制背后关键的螺旋内和螺旋间相互作用，也有助于我们理解类似物HR2模拟肽对HCoV-OC43的抑制机制。
