The coronavirus disease 2019 (COVID-19) pandemic continues worldwide with many variants arising, some of which are 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 cryoelectron microscopy structures of the omicron RBD-hACE2 complex as well as the crystal structure of the delta RBD-hACE2 complex. We found that, unlike alpha, beta, and gamma, omicron RBD binds to hACE2 at a similar affinity 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 RBD-hACE2 and delta RBD-hACE2 reveal the structural basis of how RBD-specific mutations bind to hACE2.
Display omitted
•Omicron, delta, and prototype SARS-CoV-2 RBDs show similar binding strength to hACE2•The complexes of SARS-CoV-2-RBD with hACE2 for omicron and delta variants were resolved•The roles of key residues in the omicron RBD for receptor recognition were identified
Structural analysis of the complexes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RBD with the human ACE2 receptor for omicron and delta reveals variant-specific binding features.
Monoclonal antibodies （mAbs） blocking immune checkpoint molecules, especially programmed cell death l （PD-1） and its ligands programmed cell death 1 ligand 1 （PD-L1） and ligand 2 （PD-L2）, are ...currently been in- vestigated for treatment of various tumors 1-3. PD-L1 and PD-L2 are usually upregulated on the surface of mul- tiple tumor cells to mediate immune tolerance through the interaction with inhibitory PD-1 molecule 4.
SARS-CoV-2 can infect many domestic animals, including dogs. Herein, we show that dog angiotensin-converting enzyme 2 (dACE2) can bind to the SARS-CoV-2 spike (S) protein receptor binding domain ...(RBD), and that both pseudotyped and authentic SARS-CoV-2 can infect dACE2-expressing cells. We solved the crystal structure of RBD in complex with dACE2 and found that the total number of contact residues, contact atoms, hydrogen bonds and salt bridges at the binding interface in this complex are slightly fewer than those in the complex of the RBD and human ACE2 (hACE2). This result is consistent with the fact that the binding affinity of RBD to dACE2 is lower than that of hACE2. We further show that a few important mutations in the RBD binding interface play a pivotal role in the binding affinity of RBD to both dACE2 and hACE2. Our work reveals a molecular basis for cross-species transmission and potential animal spread of SARS-CoV-2, and provides new clues to block the potential transmission chains of this virus.
The currently circulating Omicron sub-variants are the SARS-CoV-2 strains with the highest number of known mutations. Herein, we found that human angiotensin-converting enzyme 2 (hACE2) binding ...affinity to the receptor-binding domains (RBDs) of the four early Omicron sub-variants (BA.1, BA.1.1, BA.2, and BA.3) follows the order BA.1.1 > BA.2 > BA.3 ≈ BA.1. The complex structures of hACE2 with RBDs of BA.1.1, BA.2, and BA.3 reveal that the higher hACE2 binding affinity of BA.2 than BA.1 is related to the absence of the G496S mutation in BA.2. The R346K mutation in BA.1.1 majorly affects the interaction network in the BA.1.1 RBD/hACE2 interface through long-range alterations and contributes to the higher hACE2 affinity of the BA.1.1 RBD than the BA.1 RBD. These results reveal the structural basis for the distinct hACE2 binding patterns among BA.1.1, BA.2, and BA.3 RBDs.
Display omitted
•Omicron BA.1.1 and BA.2 show higher binding strength to hACE2 than the prototype and BA.1•Details in the binding interface of BA.1.1, BA.2, and BA.3.RBD with hACE2 are deciphered•R346K in BA.1.1 RBD enhances the interaction with hACE2 through long-range alterations
The biochemical and structural analysis of the human angiotensin-converting enzyme-2 (ACE2, the receptor for SARS-CoV-2 viral entry) and the receptor-binding domain (RBD) of four Omicron sub-variants—BA.1, BA.1.1, BA.2, and BA.3—helps to reveal the structural basis of differences in sub-variant binding affinities and the impact of RBD mutations.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been spreading worldwide, causing a global pandemic. Bat-origin RaTG13 is currently the most phylogenetically related virus. Here we ...obtained the complex structure of the RaTG13 receptor binding domain (RBD) with human ACE2 (hACE2) and evaluated binding of RaTG13 RBD to 24 additional ACE2 orthologs. By substituting residues in the RaTG13 RBD with their counterparts in the SARS-CoV-2 RBD, we found that residue 501, the major position found in variants of concern (VOCs) 501Y.V1/V2/V3, plays a key role in determining the potential host range of RaTG13. We also found that SARS-CoV-2 could induce strong cross-reactive antibodies to RaTG13 and identified a SARS-CoV-2 monoclonal antibody (mAb), CB6, that could cross-neutralize RaTG13 pseudovirus. These results elucidate the receptor binding and host adaption mechanisms of RaTG13 and emphasize the importance of continuous surveillance of coronaviruses (CoVs) carried by animal reservoirs to prevent another spillover of CoVs.
Display omitted
•The complex structure of RaTG13 RBD with hACE2 was determined•Binding of RaTG13 RBD to 24 additional ACE2 orthologs was evaluated•Residue 501 plays a key role in determining the potential host range of RaTG13•SARS-CoV-2 induces strong cross-protective antibodies to RaTG13 RBD
Structural and molecular analysis of the receptor binding domain of RaTG13, a coronavirus phylogenetically closely related to SARS-CoV-2, bound to the human receptor ACE2 as well as ACE2 orthologs in 24 other species provides a framework to understand its host range as well as the basis of antibody cross-reactivity between the two viruses.
SARS-CoV-2 Omicron variant has presented significant challenges to current antibodies and vaccines. Herein, we systematically compared the efficacy of 50 human monoclonal antibodies (mAbs), covering ...the seven identified epitope classes of the SARS-CoV-2 RBD, against Omicron sub-variants BA.1, BA.1.1, BA.2, and BA.3. Binding and pseudovirus-based neutralizing assays revealed that 37 of the 50 mAbs lost neutralizing activities, whereas the others displayed variably decreased activities against the four Omicron sub-variants. BA.2 was found to be more sensitive to RBD-5 antibodies than the other sub-variants. Furthermore, a quaternary complex structure of BA.1 RBD with three mAbs showing different neutralizing potencies against Omicron provided a basis for understanding the immune evasion of Omicron sub-variants and revealed the lack of G446S mutation accounting for the sensitivity of BA.2 to RBD-5 mAbs. Our results may guide the application of the available mAbs and facilitate the development of universal therapeutic antibodies and vaccines against COVID-19.
Display omitted
•Immune escape of 50 human mAbs by Omicron sub-variants was assessed•Omicron sub-variants BA.1, BA.1.1, BA.2, and BA.3 have similar immune evasion spectra•BA.2 is more sensitive to RDB-5 mAbs due to the lack of G446S mutation
The evolution of SARS-CoV-2 variants of concern brings new challenges toward host immunity and protection. Huang et al. tested the neutralization potency of 50 human mAbs against Omicron sub-variants BA.1, BA.1.1, BA.2, and BA.3. Structural analysis of three mAbs provides further insight into the immune evasion capacity of Omicron sub-variants.
•Degradation of the bond performance between composite limestone powder concretes and steel bars under a sulfate freeze–thaw environment was explored.•Contrary to slag, limestone powder and fly ash ...reduced the ultimate bond strength and increased the peak slip of split failure.•The bond performance decreased with the increase of anchorage length.•Limestone powder exacerbated the degradation of the bonding performance, while slag slowed the reduction of ultimate bond strength and corresponded with lower peak slip and more brittle failure.•The correction factor for the critical anchorage length of the sulfate freeze–thaw environment was derived.
An experimental investigation was conducted to explore the degradation of the bond performance between five types of composite limestone powder concretes and steel bars under a sulfate freeze–thaw environment. The failure model, ultimate bond strength, peak slip and bond–slip curve were researched. Three types of anchorage lengths were adopted in the investigation. The results indicated that limestone powder and fly ash reduced the ultimate bond strength and increased the peak slip of split failure. Slag increased the ultimate bond strength and reduced the peak slip. The bond performance between the composite limestone powder concrete and steel bars decreased with increasing anchorage length. Limestone powder exacerbated the degradation of the bonding performance of concrete under freeze–thaw cycles, while slag slowed the reduction in ultimate bond strength and corresponded with lower peak slip and more brittle failure. The constitutive relationship between the conventional environment τ (s, d/L) and the sulfate freeze–thaw environment τ (s, fts) was established, and the correction factor for the critical anchorage length of the sulfate freeze–thaw environment was derived. Thus, the influences of limestone powder, fly ash and slag on the critical anchorage lengths were analysed.
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the recent pandemic COVID-19, is reported to have originated from bats, with its intermediate host ...unknown to date. Here, we screened 26 animal counterparts of the human ACE2 (hACE2), the receptor for SARS-CoV-2 and SARS-CoV, and found that the ACE2s from various species, including pets, domestic animals and multiple wild animals, could bind to SARS-CoV-2 receptor binding domain (RBD) and facilitate the transduction of SARS-CoV-2 pseudovirus. Comparing to SARS-CoV-2, SARS-CoV seems to have a slightly wider range in choosing its receptor. We further resolved the cryo-electron microscopy (cryo-EM) structure of the cat ACE2 (cACE2) in complex with the SARS-CoV-2 RBD at a resolution of 3 Å, revealing similar binding mode as hACE2 to the SARS-CoV-2 RBD. These results shed light on pursuing the intermediate host of SARS-CoV-2 and highlight the necessity of monitoring susceptible hosts to prevent further outbreaks.
The origin and host range of SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19), are important scientific questions as they might provide insight into understanding of the ...potential future spillover to infect humans. Here, we tested the binding between equine angiotensin converting enzyme 2 (eqACE2) and the receptor binding domains (RBDs) of SARS-CoV, SARS-CoV-2 prototype (PT) and variant of concerns (VOCs), as well as their close relatives bat-origin coronavirus (CoV) RaTG13 and pangolin-origin CoVs GX/P2V/2017 and GD/1/2019. We also determined the crystal structures of eqACE2/RaTG13-RBD, eqACE2/SARS-CoV-2 PT-RBD and eqACE2/Omicron BA.1-RBD. We identified S494 of SARS-COV-2 PT-RBD as an important residue in the eqACE2/SARS-COV-2 PT-RBD interaction and found that N501Y, the commonly recognized enhancing mutation, attenuated the binding affinity with eqACE2. Our work demonstrates that horses are potential targets for SARS-CoV-2 and highlights the importance of continuous surveillance on SARS-CoV-2 and related CoVs to prevent spillover events.
PDF
