Structures of the Omicron spike trimer with ACE2 and an anti-Omicron antibody

Abstract

The SARS-CoV-2 Omicron variant has become the dominant infective strain. We report the structures of the Omicron spike trimer on its own or in complex with ACE2 or an anti-Omicron antibody. Most Omicron mutations are located on the surface of the spike protein, which change binding epitopes to many current antibodies. In the ACE2 binding site, compensating mutations strengthen RBD binding to ACE2. Both the RBD and the apo form of the Omicron spike trimer are thermodynamically unstable. An unusual RBD-RBD interaction in the ACE2-spike complex supports the open conformation and further reinforces ACE2 binding to the spike trimer. A broad-spectrum therapeutic antibody, JMB2002, which has completed a Phase 1 clinical trial, maintains neutralizing activity against Omicron. JMB2002 binds to RBD differently from other characterized antibodies and inhibits ACE2 binding.

Addition of arginine hydrochloride and proline to the culture medium enhances recombinant protein expression in Brevibacillus choshinensis: The case of RBD of SARS-CoV-2 spike protein and its antibody

“…We also demonstrated that the thermostability of the omicron RBD was 9 °C lower than was that of the wild-type. This observation is in agreement with a recently reported article that revealed omicron RBD expressed in mammarian cells was thermodynamically more unstable than wild-type [ 48 ]. Recently, crystal and cryoelectron microscopy structures of the omicron RBD-hACE2 complex were revealed [ 49 ].…”

SARS‐CoV‐2 Omicron variant: Immune escape and vaccine development

“…This non‐conservative substitution (uncharged amino acid to a positively charged amino acid) may impact any electrostatic interactions between the spike protein and ACE2 40,41 . Although the Omicron‐specific RBD substitutions (K417N and E484A) reduced binding of the spike protein to ACE2, other mutations that increased the affinity for ACE2 could compensate for such effects 42,43 . One example is the N501Y mutation, shared by Alpha, Beta, and Gamma variants, which enhances the binding of spike to ACE2 44,45 .…”

“… 40 , 41 Although the Omicron‐specific RBD substitutions (K417N and E484A) reduced binding of the spike protein to ACE2, other mutations that increased the affinity for ACE2 could compensate for such effects. 42 , 43 One example is the N501Y mutation, shared by Alpha, Beta, and Gamma variants, which enhances the binding of spike to ACE2. 44 , 45 Yeast surface display technology revealed that spike proteins harboring the E484K/N501Y double mutations could induce stronger affinity than the N501Y alone.…”

“…56 In summary, these mutations alter the conformation of the RBD, making Omicron easier to bind to ACE2 than SARS-CoV-2 WT, which finally makes the significantly higher transmissibility and infectivity. 42,43…”

Efficient Neutralization of SARS-CoV-2 Omicron and Other VOCs by a Broad Spectrum Antibody 8G3

“…After analyzing the cryo-EM structure of the trimeric S protein of the Omicron variant, researchers found that these mutations increased the interaction between the adjacent “up” conformation RBD and the “down” conformation RBD, making the S conformation less heterogeneous 4 . Besides, the affinity of Omicron spike protein binds to the ACE2 receptor is nearly 10 times higher than that of the wild type 5 . Cao et al investigated the activity of nine emergency use authorized (EUA) antibodies against Omicron strain and found that most of them lost neutralization, and only Sotrovimab (VIR-7831) and DXP-604 retained moderate activity with pseudovirus neutralization IC 50 s of 0.181 and 0.287 μg/mL, respectively 6 .…”