The crystal structure of coronavirus RBD-TMPRSS2 complex provides basis for the discovery of therapeutic antibodies

Zhuoqian Zhao, Qi Yang, Xiaoce Liu, Mengfei Li, Yinkai Duan, Mingjuan Du, Anqi Zhou, Huanzhen Liu, Yujia He, Wei Wang, Yuchi Lu, Xiaoyu Zhang, Haofeng Wang, Xiuna Yang (), Hongkai Zhang (), Xinwen Chen (), Zihe Rao and Haitao Yang ()
Additional contact information
Zhuoqian Zhao: ShanghaiTech University
Qi Yang: Guangzhou Laboratory
Xiaoce Liu: ShanghaiTech University
Mengfei Li: ShanghaiTech University
Yinkai Duan: ShanghaiTech University
Mingjuan Du: ShanghaiTech University
Anqi Zhou: Guangzhou Laboratory
Huanzhen Liu: ShanghaiTech University
Yujia He: ShanghaiTech University
Wei Wang: ShanghaiTech University
Yuchi Lu: ShanghaiTech University
Xiaoyu Zhang: ShanghaiTech University
Haofeng Wang: ShanghaiTech University
Xiuna Yang: ShanghaiTech University
Hongkai Zhang: ShanghaiTech University
Xinwen Chen: Guangzhou Laboratory
Zihe Rao: Tsinghua University
Haitao Yang: ShanghaiTech University

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract HCoV-HKU1, one of seven human coronaviruses (HCoVs) that have harmful effects on human health, accounts for a substantial portion of common cold cases and can cause severe respiratory diseases in certain populations. Currently, effective antiviral treatments against this virus are limited. Recently, TMPRSS2, a host protease long acknowledged for its role in priming the spike proteins of various CoVs and promoting viral entry, was identified as a functional receptor for HCoV-HKU1, opening an avenue for anti-HCoV-HKU1 therapy development. In this study, we elucidate the detailed molecular mechanism underlying the interaction between the HCoV-HKU1 receptor-binding domain (RBD) and TMPRSS2 via crystallography. Guided by these structural insights, we successfully develop two types of therapeutic antibodies against HCoV-HKU1. The first type neutralizes the RBD, potently disrupting its interaction with TMPRSS2 and preventing viral infection. The second type targets TMPRSS2, inhibiting its enzymatic activity and/or interfering with its binding to the RBD. The latter demonstrates broad-spectrum anti-CoV activity, as the enzymatic activity of TMPRSS2 is crucial for both HCoV-HKU1 infection and other CoV infections. Our findings provide crucial structural insights into the recognition of TMPRSS2 by HCoV-HKU1 and offer promising antibody-based strategies for combating HCoV-HKU1 and other CoV infections.

Date: 2025
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DOI: 10.1038/s41467-025-62023-2

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