2024年7月3日出版的《细胞》杂志发表了美国华盛顿大学David Veesler研究组的最新成果,他们提出了人冠状病毒HKU1对TMPRSS2宿主受体的识别。
该研究组设计了一个活性人类TMPRSS2构建体,使得在人体细胞中高效重组生产这一关键治疗靶点成为可能。研究人员确定了HKU1 RBD与人类TMPRSS2结合的低温电镜结构,提供了支持病毒进入的相互作用蓝图,并解释了TMPRSS2在同源蛋白酶中的特异性。
该课题组人员从5个哺乳动物目中鉴定出TMPRSS2同源物,这些同源物促进HKU1刺突-介导的细胞进入,以及控制宿主受体使用的关键残基。他们的数据表明,TMPRSS2结合基序是一个易受中和抗体影响的位点,并表明HKU1通过刺突构象掩蔽和聚糖屏蔽来平衡免疫逃避和受体结合。
据介绍,人冠状病毒HKU1刺突(S)糖蛋白与宿主细胞表面唾液聚糖和跨膜蛋白酶丝氨酸2 (TMPRSS2)结合引发感染。HKU1与TMPRSS2结合的分子基础和宿主受体趋向性的决定因素尚不清楚。
附:英文原文
Title: Human coronavirus HKU1 recognition of the TMPRSS2 host receptor
Author: Matthew McCallum, Young-Jun Park, Cameron Stewart, Kaitlin R. Sprouse, Amin Addetia, Jack Brown, M. Alejandra Tortorici, Cecily Gibson, Emily Wong, Margareta Ieven, Amalio Telenti, David Veesler
Issue&Volume: 2024-07-03
Abstract: The human coronavirus HKU1 spike (S) glycoprotein engages host cell surface sialoglycans and transmembrane protease serine 2 (TMPRSS2) to initiate infection. The molecular basis of HKU1 binding to TMPRSS2 and determinants of host receptor tropism remain elusive. We designed an active human TMPRSS2 construct enabling high-yield recombinant production in human cells of this key therapeutic target. We determined a cryo-electron microscopy structure of the HKU1 RBD bound to human TMPRSS2, providing a blueprint of the interactions supporting viral entry and explaining the specificity for TMPRSS2 among orthologous proteases. We identified TMPRSS2 orthologs from five mammalian orders promoting HKU1 S-mediated entry into cells along with key residues governing host receptor usage. Our data show that the TMPRSS2 binding motif is a site of vulnerability to neutralizing antibodies and suggest that HKU1 uses S conformational masking and glycan shielding to balance immune evasion and receptor engagement.
DOI: 10.1016/j.cell.2024.06.006
Source: https://www.cell.com/cell/fulltext/S0092-8674(24)00646-9