Receptor binding and complex structures of human ACE2 to spike RBD from omicron and delta SARS-CoV-2

Abstract

COVID-19 pandemic continues worldwide with many variants arising, especially those of variants of concern (VOCs). A recent VOC, Omicron (B.1.1.529), which obtains a large number of mutations in the receptor-binding domain (RBD) of the spike protein, has risen to intense scientific and public attention. Here we studied the binding properties between the human receptor ACE2 (hACE2) and the VOC RBDs and resolved the crystal and cryo- EM structures of the Omicron RBD-hACE2 complex, as well as the crystal structure of Delta RBD-hACE2 complex. We found that, unlike Alpha, Beta and Gamma, Omicron RBD binds to hACE2 at a similar affinity compared to that of the prototype RBD, which might be due to compensation of multiple mutations for both immune escape and transmissibility. The complex structures of Omicron-hACE2 and Delta-hACE2 reveal the structural basis of how RBD-specific mutations bind to hACE2.

COVID-19 Omicron variant-inhibitory in silico evidence for phytocompounds of an ancient Ayurvedic formulation

“…Delta mutations, L452R front of the neck, T478K far side of left shoulder, fall just peripheral to the ACE2 binding footprint (Figure 1A) (Han et al, 2022). Omicron shares at least one RBD mutation with all of these variants.…”

Omicron variant of SARS-CoV-2 imposes a new challenge for the global public health

“…Alarmingly, the Omicron variant carries an unusual number of mutations, particularly on the spike (S) protein including the receptor-binding domain (RBD), which might lead to altered transmissibility and immune escapes [2] . Population-level evidence showed an association between the emergence of Omicron and a higher risk of reinfection, indicating its ability to evade immunity from prior infection [1] .…”

“…Moreover, a recent study demonstrated that K417N mutation led to reduced cellular immune responses [8] . However, structural analysis showed that K417N might moderately decrease binding affinity of human ACE2 [2] , indicating an evolutionary trade-off between infectivity and immune escape.…”

“…SARS-CoV-2 mutants with N501Y mutation could break the interspecies barrier and infect mice. Subsequently, mouse-adapted strains emerged, with Q498H, Q493K or Q493H mutations, which increased the binding affinity to hACE2 [2] . Besides, Q493Y and Q498Y influenced the host range [12] .…”

From Free Binding Energy Calculations of SARS-CoV-2—Receptor Interactions to Cellular Immune Responses

“…As of yet, binding strength differences of SARS-CoV-2 VOCs' spike proteins to hACE2 are estimated controversially, depending on molecular modelling and simulation approaches [19][20][21][22][23][24]. Experimental data on binding strengths of SARS-CoV-2 Omicron's spike protein to hACE2 which so far have become available provide evidence that Omicron's RBD interaction with hACE2 is weaker than that of Delta's RBD [25][26][27], with one exception which states that binding strength of Delta's or Omicron's RBD to hACE2 was in similar ranges [28].…”