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Nat Commun
. 2025 Jul 18;16(1):6636.
doi: 10.1038/s41467-025-62023-2. The crystal structure of coronavirus RBD-TMPRSS2 complex provides basis for the discovery of therapeutic antibodies
Zhuoqian Zhao # 1 2 3 , Qi Yang # 4 , Xiaoce Liu # 1 2 , Mengfei Li # 1 2 , Yinkai Duan # 1 2 , Mingjuan Du 1 , Anqi Zhou 4 , Huanzhen Liu 1 , Yujia He 1 2 , Wei Wang 1 , Yuchi Lu 1 2 3 , Xiaoyu Zhang 1 2 3 , Haofeng Wang 1 2 , Xiuna Yang 5 6 , Hongkai Zhang 7 8 , Xinwen Chen 9 , Zihe Rao 10 , Haitao Yang 11 12
Affiliations
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.
. 2025 Jul 18;16(1):6636.
doi: 10.1038/s41467-025-62023-2. The crystal structure of coronavirus RBD-TMPRSS2 complex provides basis for the discovery of therapeutic antibodies
Zhuoqian Zhao # 1 2 3 , Qi Yang # 4 , Xiaoce Liu # 1 2 , Mengfei Li # 1 2 , Yinkai Duan # 1 2 , Mingjuan Du 1 , Anqi Zhou 4 , Huanzhen Liu 1 , Yujia He 1 2 , Wei Wang 1 , Yuchi Lu 1 2 3 , Xiaoyu Zhang 1 2 3 , Haofeng Wang 1 2 , Xiuna Yang 5 6 , Hongkai Zhang 7 8 , Xinwen Chen 9 , Zihe Rao 10 , Haitao Yang 11 12
Affiliations
- PMID: 40681508
- PMCID: PMC12274457
- DOI: 10.1038/s41467-025-62023-2
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.