| Autor: |
Sluchanko NN; Bach Institute of Biochemistry, Federal Research Centre 'Fundamentals of Biotechnology', Russian Academy of Sciences, Moscow, 119071, Russia. nikolai.sluchanko@mail.ru.; National Research Center for Epidemiology and Microbiology named after Honorary Academician N. F. Gamaleya, Ministry of Health of the Russian Federation, Moscow, 123098, Russia., Shcheblyakov DV; National Research Center for Epidemiology and Microbiology named after Honorary Academician N. F. Gamaleya, Ministry of Health of the Russian Federation, Moscow, 123098, Russia. sdmitriyv@mail.ru., Varfolomeeva LA; Bach Institute of Biochemistry, Federal Research Centre 'Fundamentals of Biotechnology', Russian Academy of Sciences, Moscow, 119071, Russia., Favorskaya IA; National Research Center for Epidemiology and Microbiology named after Honorary Academician N. F. Gamaleya, Ministry of Health of the Russian Federation, Moscow, 123098, Russia., Dolzhikova IV; National Research Center for Epidemiology and Microbiology named after Honorary Academician N. F. Gamaleya, Ministry of Health of the Russian Federation, Moscow, 123098, Russia., Korobkova AI; National Research Center for Epidemiology and Microbiology named after Honorary Academician N. F. Gamaleya, Ministry of Health of the Russian Federation, Moscow, 123098, Russia., Alekseeva IA; National Research Center for Epidemiology and Microbiology named after Honorary Academician N. F. Gamaleya, Ministry of Health of the Russian Federation, Moscow, 123098, Russia., Esmagambetov IB; National Research Center for Epidemiology and Microbiology named after Honorary Academician N. F. Gamaleya, Ministry of Health of the Russian Federation, Moscow, 123098, Russia., Derkaev AA; National Research Center for Epidemiology and Microbiology named after Honorary Academician N. F. Gamaleya, Ministry of Health of the Russian Federation, Moscow, 123098, Russia., Prokofiev VV; National Research Center for Epidemiology and Microbiology named after Honorary Academician N. F. Gamaleya, Ministry of Health of the Russian Federation, Moscow, 123098, Russia., Zorkov ID; National Research Center for Epidemiology and Microbiology named after Honorary Academician N. F. Gamaleya, Ministry of Health of the Russian Federation, Moscow, 123098, Russia., Logunov DY; National Research Center for Epidemiology and Microbiology named after Honorary Academician N. F. Gamaleya, Ministry of Health of the Russian Federation, Moscow, 123098, Russia., Gintsburg AL; National Research Center for Epidemiology and Microbiology named after Honorary Academician N. F. Gamaleya, Ministry of Health of the Russian Federation, Moscow, 123098, Russia., Popov VO; Bach Institute of Biochemistry, Federal Research Centre 'Fundamentals of Biotechnology', Russian Academy of Sciences, Moscow, 119071, Russia., Boyko KM; Bach Institute of Biochemistry, Federal Research Centre 'Fundamentals of Biotechnology', Russian Academy of Sciences, Moscow, 119071, Russia. kmb@inbi.ras.ru.; National Research Center for Epidemiology and Microbiology named after Honorary Academician N. F. Gamaleya, Ministry of Health of the Russian Federation, Moscow, 123098, Russia. |
| Abstrakt: |
COVID-19 has caused millions of deaths and many times more infections worldwide, emphasizing the unpreparedness of the global health system in the face of new infections and the key role for vaccines and therapeutics, including virus-neutralizing antibodies, in prevention and containment of the disease. Continuous evolution of the SARS-CoV-2 coronavirus has been causing its new variants to evade the action of the immune system, which highlighted the importance of detailed knowledge of the epitopes of already selected potent virus-neutralizing antibodies. A single-chain antibody ("nanobody") targeting the SARS-CoV-2 receptor-binding domain (RBD), clone P2C5, had exhibited robust virus-neutralizing activity against all SARS-CoV-2 variants and, being a major component of the anti-COVID-19 formulation "GamCoviMab", had successfully passed Phase I of clinical trials. However, after the emergence of the Delta and XBB variants, a decrease in the neutralizing activity of this nanobody was observed. Here we report on the successful crystal structure determination of the RBD:P2C5 complex at 3.1 Å, which revealed the intricate protein-protein interface, sterically occluding full ACE2 receptor binding by the P2C5-neutralized RBD. Moreover, the structure revealed the developed RBD:P2C5 interface centered around residues Leu452 and Phe490, thereby explaining the evasion of the Delta or Omicron XBB, but not Omicron B.1.1.529 variant, as a result of the single L452R or F490S mutations, respectively, from the action of P2C5. The structure obtained is expected to foster nanobody engineering in order to rescue neutralization activity and will facilitate epitope mapping for other neutralizing nanobodies by competition assays. |
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