法国巴斯德研究所Félix A. Rey和Olivier Schwartz课题组取得一项新突破。他们提出了HKU1季节性冠状病毒激活和识别TMPRSS2酶原的结构基础。2024年7月3日出版的《细胞》杂志发表了这项成果。

该课题组描述了HKU1-CoV受体结合域与TMPRSS2复合物的晶体结构，表明它可以识别催化槽内的残基。界面残基的联合诱变和跨物种比较突出了417和469位点是HKU1-CoV宿主趋向性的决定因素。受体阻断纳米体与酶原或活化TMPRSS2复合物的结构进一步为TMPRSS2激活构象变化提供了结构基础，从而改变HKU1-CoV识别的环，显著提高结合亲和力。

研究人员表示，引起全球普通感冒的人类季节性冠状病毒HKU1-CoV依赖于顺序结合表面糖链和跨膜丝氨酸蛋白酶2（TMPRSS2）进入靶细胞。TMPRSS2作为一种酶原合成，经过自溶激活来加工其底物。一些呼吸道病毒主题，特别是冠状病毒，使用TMPRSS2蛋白水解引发其表面刺突蛋白，以驱动受体结合时的膜氧化。

附：英文原文

Title: Structural basis of TMPRSS2 zymogen activation and recognition by the HKU1 seasonal coronavirus

Author: Ignacio Fernández, Nell Saunders, Stéphane Duquerroy, William H. Bolland, Atousa Arbabian, Eduard Baquero, Catherine Blanc, Pierre Lafaye, Ahmed Haouz, Julian Buchrieser, Olivier Schwartz, Félix A. Rey

Issue&Volume: 2024-07-03

Abstract: The human seasonal coronavirus HKU1-CoV, which causes common colds worldwide, relieson 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 autolyticactivation to process its substrates. Several respiratory viruses, in particular coronaviruses,use TMPRSS2 for proteolytic priming of their surface spike protein to drive membranefusion upon receptor binding. We describe the crystal structure of the HKU1-CoV receptorbinding domain in complex with TMPRSS2, showing that it recognizes residues liningthe catalytic groove. Combined mutagenesis of interface residues and comparison acrossspecies highlight positions 417 and 469 as determinants of HKU1-CoV host tropism.The structure of a receptor-blocking nanobody in complex with zymogen or activatedTMPRSS2 further provides the structural basis of TMPRSS2 activating conformationalchange, which alters loops recognized by HKU1-CoV and dramatically increases bindingaffinity.

DOI: 10.1016/j.cell.2024.06.007

Source: https://www.cell.com/cell/abstract/S0092-8674(24)00647-0