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Zech, Fabian; Schniertshauer, Daniel; Jung, Christoph; Herrmann, Alexandra; Cordsmeier, Arne; Xie, Qinya; Nchioua, Rayhane; Bozzo, Caterina Prelli; Volcic, Meta; Koepke, Lennart; Mueller, Janis A.; Krueger, Jana; Heller, Sandra; Stenger, Steffen; Hoffmann, Markus; Poehlmann, Stefan; Kleger, Alexander; Jacob, Timo; Conzelmann, Karl-Klaus; Ensser, Armin; Sparrer, Konstantin M. J. and Kirchhoff, Frank (2021): Spike residue 403 affects binding of coronavirus spikes to human ACE2. In: Nature Communications, Vol. 12, No. 1, 6855

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The bat sarbecovirus RaTG13 is a close relative of SARS-CoV-2, the cause of the COVID-19 pandemic. However, this bat virus was most likely unable to directly infect humans since its Spike (S) protein does not interact efficiently with the human ACE2 receptor. Here, we show that a single T403R mutation increases binding of RaTG13 S to human ACE2 and allows VSV pseudoparticle infection of human lung cells and intestinal organoids. Conversely, mutation of R403T in the SARS-CoV-2 S reduces pseudoparticle infection and viral replication. The T403R RaTG13 S is neutralized by sera from individuals vaccinated against COVID-19 indicating that vaccination might protect against future zoonoses. Our data suggest that a positively charged amino acid at position 403 in the S protein is critical for efficient utilization of human ACE2 by S proteins of bat coronaviruses. This finding could help to better predict the zoonotic potential of animal coronaviruses. The bat sarbecovirus RaTG13 is a close relative of SARS-CoV-2, but its spike protein doesn't efficiently bind human ACE2. Here, the authors show that exchange of spike residue 403 between RaTG13 and SARS-CoV-2 spike proteins affects binding to human ACE2 and entry of pseudotyped viruses.

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