Abstract：
The human seasonal coronavirus HKU1-CoV, which causes common colds worldwide, relies on the sequential binding to surface glycans and transmembrane serine protease 2 (TMPRSS2) for entry into target cells. TMPRSS2 is synthesized as a zymogen that undergoes autolytic activation to process its substrates. Several respiratory viruses, in particular coronaviruses, use TMPRSS2 for proteolytic priming of their surface spike protein to drive membrane fusion upon receptor binding. We describe the crystal structure of the HKU1-CoV receptor binding domain in complex with TMPRSS2, showing that it recognizes residues lining the catalytic groove. Combined mutagenesis of interface residues and comparison across species highlight positions 417 and 469 as determinants of HKU1-CoV host tropism. The structure of a receptor-blocking nanobody in complex with zymogen or activated TMPRSS2 further provides the structural basis of TMPRSS2 activating conformational change, which alters loops recognized by HKU1-CoV and dramatically increases binding affinity.
摘要：
人类季节性冠状病毒HKU1-CoV，导致全球常见的感冒，依赖于与表面聚糖和跨膜丝氨酸蛋白酶2（TMPRSS2）的顺序结合以进入靶细胞。TMPRSS2作为酶原合成,其经历自溶活化以处理其底物。几种呼吸道病毒，特别是冠状病毒，使用TMPRSS2对其表面刺突蛋白进行蛋白水解引发，以在受体结合时驱动膜融合。我们描述了与TMPRSS2复合的HKU1-CoV受体结合域的晶体结构，表明它可以识别催化沟衬里的残基。界面残基的联合诱变和物种间的比较突出了位置417和469是HKU1-CoV宿主嗜性的决定因素。与酶原或激活的TMPRSS2复合的受体阻断纳米抗体的结构进一步提供了TMPRSS2激活构象变化的结构基础，其改变由HKU1-CoV识别的环并显著增加结合亲和力。
