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2024

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Gao Fu/Qi Jianxun/Fan Zheng Cooperation Latest EMBO J

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Since the emergence of the SARS-CoV-2Omicron variant, it has evolved into several subvariants, including BF. 7. BQ. 1. BQ. 1.1, XBB, XBB. 1.5 and more recently BA. 2.86 and JN. 1.Receptor binding and immune evasion are considered to be the two major drivers of the evolution of the receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) protein. However, the mechanisms underlying the interaction between the two factors are still not fully understood.
On March 11, 2024, Gao Fu, Qi Jianxun and Fan Zheng of the Chinese Academy of Sciences jointly communicated in The EMBO Journal Published online entitled “ Key mechanistic features of the trade-off between antibody escape and host cell binding in the SARS-CoV-2 Omicron variant spike proteins ”The research paper, Human ACE2 and BF were identified in this study. 7. BQ. 1. BQ. 1.1, XBB and XBB. 1.5 the structure of RBDs complexes.

Based on the ACE2/RBD structures of these subvariants and comparing with known complex structures, the authors found that the R346T substitution in RBD enhances ACE2 binding that interacts with residue R493, but not Q493, through a mechanism involving long-range conformational changes.In addition, the authors found that R493Q and F486V play a balancing role by which immune evasion is compromised for optimal receptor binding.The authors propose a "two steps forward and further back" model to describe this compromise between receptor binding affinity and immune evasion during the evolution of Omicron subvariant RBDs.

Since its announcement on 26 November 2021, the fifth SARS-CoV-2 Variant (VOC)Omicron(B .1.1.529) has spread rapidly around the world.Worryingly, the virus continues to evolve to adapt to the host, with subvariants emerging rapidly in succession, including BF. 7. BQ. 1. BQ. 1.1, XBB, XBB. 1.5. BA. 2.86 and JN. 1 . Despite considerable efforts to develop vaccines and monoclonal antibodies (MAbs) to establish herd immunity, newly emerging subvariants are constantly adapted to the current immune context and exhibit further immune evasion.

Receptor binding and immune escape are thought to be the two major drivers of the evolution of the viral spike (S) protein receptor-binding domain (RBD), which is responsible for receptor recognition.Studies have found that the occurrence of new RBD mutations is associated with both receptor binding and immune escape, and recent quantitative studies have shown that the latter is more significantly associated with the occurrence of mutations. The interaction between the two factors has received widespread attention, and the study found that the affinity-enhancing mutation N501Y and the immune escape mutation are epistopic, indicating that the two driving forces are intertwined. Cao et al. further combined ACE2 binding capacity, codon usage restrictions, and immune escape profiles to estimate the evolutionary trend of RBD.However, the specific mechanism of the interaction between the two factors is not clear.

Receptor binding properties of SARS-CoV-2 Omicron subvariants

Since the emergence of VOCs, the authors and others have continuously monitored the receptor binding properties of VOCs, especially the major Omicron subvariants.R493Q reversal has been noted to significantly enhance receptor binding but may be detrimental to immune evasion. Based on these results, the authors hypothesized that R493Q reversal is a compromise between receptor binding and immune evasion.
In the present study, the authors evaluated BF. 7. BQ. 1. BQ. 1.1, XBB and XBB. 1.5RBD and human ACE2(hACE2) binding characteristics, and determine the hACE2 and BF, respectively. 7. BQ. 1. BQ. 1.1, XBB and XBB. 1.5 Cryo-electron microscopy structure of the RBD complex.From the structure, the authors found that R493, but not Q493, is regulated by R346T substitution through long-range conformational changes. In addition, the authors found that RBD from BA. The mutation of 2 to BA4/5 appears to be a compromise between receptor binding and immune evasion. These results enhance the authors' understanding of the relationship between receptor binding and immune evasion for these Omicron subvariants.

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NAR | Tsinghua University Zhang Qiyi team designed and verified a CRISPR activation system and anti-CRISPR protein to establish adaptability in mammalian cells

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NAR | Zhejiang University Ren Aiming's team elucidated important long-range interactions that control the function of THF-II riboswitches and identified other compounds that interact with THF-II riboswitches

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