Structure and dynamics of the interaction of Delta and Omicron BA.1 SARS-CoV-2 variants with REGN10987 Fab reveal mechanism of antibody action.

Autor: Lyukmanova EN; Department of Biology, Shenzhen MSU-BIT University, Shenzhen, China. lyukmanova_ekaterina@smbu.edu.cn.; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia. lyukmanova_ekaterina@smbu.edu.cn.; Interdisciplinary Scientific and Educational School of Moscow University 'Molecular Technologies of the Living Systems and Synthetic Biology', Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia. lyukmanova_ekaterina@smbu.edu.cn., Pichkur EB; Department of Molecular and Radiation Biophysics, Petersburg Nuclear Physics Institute named by B.P.Konstantinov of National Research Center 'Kurchatov Institute', Gatchina, Russia., Nolde DE; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia., Kocharovskaya MV; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia., Manuvera VA; Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia., Shirokov DA; Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia., Kharlampieva DD; Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia., Grafskaia EN; Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia., Svetlova JI; Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia., Lazarev VN; Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia., Varizhuk AM; Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia., Kirpichnikov MP; Department of Biology, Shenzhen MSU-BIT University, Shenzhen, China.; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia.; Interdisciplinary Scientific and Educational School of Moscow University 'Molecular Technologies of the Living Systems and Synthetic Biology', Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia., Shenkarev ZO; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia. zakhar-shenkarev@yandex.ru.
Jazyk: angličtina
Zdroj: Communications biology [Commun Biol] 2024 Dec 24; Vol. 7 (1), pp. 1698. Date of Electronic Publication: 2024 Dec 24.
DOI: 10.1038/s42003-024-07422-9
Abstrakt: Study of mechanisms by which antibodies recognize different viral strains is necessary for the development of new drugs and vaccines to treat COVID-19 and other infections. Here, we report 2.5 Å cryo-EM structure of the SARS-CoV-2 Delta trimeric S-protein in complex with Fab of the recombinant analog of REGN10987 neutralizing antibody. S-protein adopts "two RBD-down and one RBD-up" conformation. Fab interacts with RBDs in both conformations, blocking the recognition of angiotensin converting enzyme-2. Three-dimensional variability analysis reveals high mobility of the RBD/Fab regions. Interaction of REGN10987 with Wuhan, Delta, Omicron BA.1, and mutated variants of RBDs is analyzed by microscale thermophoresis, molecular dynamics simulations, and ΔG calculations with umbrella sampling and one-dimensional potential of mean force. Variability in molecular dynamics trajectories results in a large scatter of calculated ΔG values, but Boltzmann weighting provides an acceptable correlation with experiment. REGN10987 evasion of the Omicron variant is found to be due to the additive effect of the N440K and G446S mutations located at the RBD/Fab binding interface with a small effect of Q498R mutation. Our study explains the influence of known-to-date SARS-CoV-2 RBD mutations on REGN10987 recognition and highlights the importance of dynamics data beyond the static structure of the RBD/Fab complex.
Competing Interests: Competing interests: The authors declare no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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