9kwy
Cryo-EM structure of SARS-CoV-2 RBD in complex with ACE2 and mAb 1C4
Structural highlights
FunctionACE2_FELCA Essential counter-regulatory carboxypeptidase of the renin-angiotensin hormone system that is a critical regulator of blood volume, systemic vascular resistance, and thus cardiovascular homeostasis. Converts angiotensin I to angiotensin 1-9, a nine-amino acid peptide with anti-hypertrophic effects in cardiomyocytes, and angiotensin II to angiotensin 1-7, which then acts as a beneficial vasodilator and anti-proliferation agent, counterbalancing the actions of the vasoconstrictor angiotensin II. Also removes the C-terminal residue from three other vasoactive peptides, neurotensin, kinetensin, and des-Arg bradykinin, but is not active on bradykinin. Also cleaves other biological peptides, such as apelins, casomorphins and dynorphin A. Plays an important role in amino acid transport by acting as binding partner of amino acid transporter SLC6A19 in intestine, regulating trafficking, expression on the cell surface, and its catalytic activity.[UniProtKB:Q9BYF1] Publication Abstract from PubMedThe rapid evolution of SARS-CoV-2 and the subsequent emergence of Omicron subvariants pose significant challenges to the efficacy of existing vaccines and therapeutics, including those previously reported most broad neutralizing antibodies (bnAbs). Here, we investigated the molecular basis of the altered neutralization profile of a bnAb, 1C4, against recent variants. 1C4 is effective against early variants from Alpha to Omicron BQ.1, but is circumvented by BQ.1.1, XBB and thereafter variants, primarily due to an additional R346T mutation that diminishes its binding affinity. Cryo-electron microscopy analysis revealed that despite the loss of neutralizing potency, 1C4 retained residual binding to the spike protein of immune-evasive variants such as XBB, which harbor altered receptor-binding domain (RBD). Furthermore, 1C4 exhibited a diminished capacity to inhibit ACE2 engagement with Omicron variants, amplifying the intricacies of viral immune evasion tactics. To address this, we employed the mi3-SpyCatcher-based nanoparticle to polymerize 1C4 (mi3-1C4), which reestablished the neutralization potency against recent variants by enhancing avidity via multivalent binding. Such multivalent binding can promote efficient spike aggregation as well as viral cross-linking, thereby providing enhanced protection against both the infection of Beta and XBB variants in a hamster model. Together, our findings delineate the molecular landscape of immune evasion by neutralizing antibodies and provide strategic insight for the adaptation of antibody engineering to keep pace with viral evolution. Engineering a multivalent antibody nanoparticle to overcome SARS-CoV-2 Omicron immune evasion.,Sun H, Jiang Y, Lan M, Zhou M, Yi G, Shen J, Deng T, Liu L, Huang Y, Li Y, Su J, Lin Y, Chen Z, Zhou L, Li T, Yu H, Cheng T, Zhang Y, Yuan L, Li S, Gu Y, Zhang P, Xia N, Zheng Q PLoS Pathog. 2025 Dec 8;21(12):e1013744. doi: 10.1371/journal.ppat.1013744. , eCollection 2025 Dec. PMID:41359663[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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