Molecular insights into receptor binding of recent emerging SARS-CoV-2 variants

Han, Pengcheng; Su, Chao; Zhang, Yanfang; Bai, C. H.; Zheng, Anqi; Qiao, Chengpeng; Wang, Qing; Niu, Sheng; Qian, Chen; Zhang, Yuqin; Li, Weiwei; Liao, Hanyi; Li, Jing; Zhang, Zengyuan; Cho, Heecheol; Yang, Moon-Sik; Rong, Xiaoyu; Hu, Yu; Huang, Niu; Yan, Jinghua; Wang, Qihui; Zhao, Xin; Gao, George F.; Qi, Jianxun

doi:10.1038/s41467-021-26401-w

Cited by 149 publications

(170 citation statements)

References 55 publications

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“…This could explain the results that we observed in the mink farm. Apart from that, N501T mutation, which is also found in all our mink sequences, has been described recently to have higher affinity to human ACE2 receptor (32). However, its relationship with the severity of the disease is still to be determined.…”

Section: Discussionmentioning

confidence: 73%

SARS-CoV-2 Outbreak on a Spanish Mink Farm: Epidemiological, Molecular, and Pathological Studies

et al. 2022

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Farmed minks have been reported to be highly susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and may represent a risk to humans. In this study, we describe the first outbreak of SARS-CoV-2 occurred on a mink farm in Spain, between June and July 2020, involving 92,700 animals. The outbreak started shortly after some farm workers became seropositive for SARS-CoV-2. Minks showed no clinical signs compatible with SARS-CoV-2 infection throughout the outbreak. Samples from 98 minks were collected for histopathological, serological, and molecular studies. Twenty out of 98 (20.4%) minks were positive by RT-qPCR and 82 out 92 (89%) seroconverted. This finding may reflect a rapid spread of the virus at the farm with most of the animals overcoming the infection. Additionally, SARS-CoV-2 was detected by RT-qPCR in 30% of brain samples from positive minks. Sequencing analysis showed that the mink sequences were not closely related with the other mink SARS-CoV-2 sequences available, and that this mink outbreak has its probable origin in one of the genetic variants that were prevalent in Spain during the first COVID-19 epidemic wave. Histological studies revealed bronchointerstitial pneumonia in some animals. Immunostaining of viral nucleocapsid was also observed in nasal turbinate tissue. Farmed minks could therefore constitute an important SARS-CoV-2 reservoir, contributing to virus spread among minks and humans. Consequently, continuous surveillance of mink farms is needed.

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Section: Discussionmentioning

confidence: 73%

SARS-CoV-2 Outbreak on a Spanish Mink Farm: Epidemiological, Molecular, and Pathological Studies

et al. 2022

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“…Mutations in the beta variant make it more transmissible, with greater antibody resistance, higher risk of hospitalization, ICU admission, and death compared to earlier SARS-CoV-2 E variants (Veneti et al, 2021; Wang et al, 2021). In addition to the P71L mutation, the beta variant has other mutations, including three on its spike protein, which may help the virus to escape antibodies and to bind more tightly to human cells (Han et al, 2021). The importance of the P71L mutation in the greater pathogenicity of the beta variant remains to be demonstrated.…”

Section: Discussionmentioning

confidence: 99%

Interactions of SARS-CoV-2 protein E with cell junctions and polarity PDZ-containing proteins

Zhu

Alvarez

Wolff

et al. 2021

Preprint

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The C-terminus of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protein E contains a PBM (PDZ binding motif) targeting PDZ (PSD-95/Dlg/ZO-1) domains identical to the PBM of SARS-CoV. The latter is involved in the pathogenicity of the virus. Recently, we identified ten human PDZ-containing proteins showing significant interactions with SARS-CoV-2 protein E PBM. We selected several of them involved in cellular junctions and cell polarity (TJP1, PARD3, MLLT4, LNX2) and MPP5/Pals1 previously shown to interact with SARS-CoV E PBM. Targeting cellular junctions and polarity components is a common strategy by viruses to hijack cell machinery to their advantage. In this study, we showed that these host PDZ domains TJP1, PARD3, MLLT4, LNX2 and MPP5/PALS1 interact in a PBM-dependent manner in vitro and colocalize with the full-length E protein in cellulo, sequestrating the PDZ domains to the Golgi compartment. We solved three crystal structures of complexes between human LNX2, MLLT4 and MPP5 PDZs and SARS-CoV-2 E PBM highlighting its binding preferences for several cellular targets. Finally, we showed different affinities for the PDZ domains with the original SARS-CoV-2 C-terminal sequence containing the PBM and the one of the beta variant that contains a mutation close to the PBM. The acquired mutations in E protein localized near the PBM might have important effects both on the structure and the ion-channel activity of the E protein and on the host machinery targeted by the variants during the infection.

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“…The original asparagine is a contact residue with ACE2, forming a hydrogen bond with tyrosine 41 (Y41) of ACE2. The N501Y mutation lost this hydrogen bond; however, it created a much stronger interaction via p-p stacking, formed between 501Y of spike and 41Y of ACE2, and also cation-p interaction between 501Y and lysine 353 of ACE2 (Figure 1B) (22). These newly formed interactions increased ACE2 binding affinity by 10-fold compared with the ancestral RBD, contributed by a 1.3-time faster association rate and a 7.7-time slower dissociation rate (18).…”

Section: Alpha Variantmentioning

confidence: 99%

“…Currently, WHO has five SARS-CoV-2 variants of concern (VOC), Alpha, Beta, Gamma, Delta, and Omicron, and two SARS-CoV-2 variants of interest (VOI), Lambda and Mu (WHO SARS-CoV-2 Variants). These variants affect the binding of the viral RBD to ACE2, and/or the infectivity of the virus, and/or neutralization of the virus by mAbs to different degrees while maintaining the overall structure of the spike (Table 1) (18)(19)(20)(21)(22). The three RBD mutations, for example, in the Beta, Gamma, or Mu variants do not change the overall structure of the RBD from the ancestral version (Figure 1A) (22) and a low root-mean-square deviation (RMSD) between the Beta variant RBD and the ancestral RBD of 0.62 indicates the three mutations have little effect on the overall backbone of RBD.…”

Section: Introductionmentioning

confidence: 99%

“…These variants affect the binding of the viral RBD to ACE2, and/or the infectivity of the virus, and/or neutralization of the virus by mAbs to different degrees while maintaining the overall structure of the spike (Table 1) (18)(19)(20)(21)(22). The three RBD mutations, for example, in the Beta, Gamma, or Mu variants do not change the overall structure of the RBD from the ancestral version (Figure 1A) (22) and a low root-mean-square deviation (RMSD) between the Beta variant RBD and the ancestral RBD of 0.62 indicates the three mutations have little effect on the overall backbone of RBD. However, they do affect the binding of at least one of the mAbs since its target on the RBD overlaps with a mutated amino acid (Figure 2A).…”

Section: Introductionmentioning

confidence: 99%

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SARS-CoV-2 Variants of Concern and Variants of Interest Receptor Binding Domain Mutations and Virus Infectivity

et al. 2022

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has lasted more than 2 years with over 260 million infections and 5 million deaths worldwide as of November 2021. To combat the virus, monoclonal antibodies blocking the virus binding to human receptor, the angiotensin converting enzyme 2 (ACE2), have been approved to treat the infected patients. Inactivated whole virus or the full-length virus spike encoding adenovirus or mRNA vaccines are being used to immunize the public. However, SARS-CoV-2 variants are emerging. These, to some extent, escape neutralization by the therapeutic antibodies and vaccine-induced immunity. Thus, breakthrough infections by SARS-CoV-2 variants have been reported in previously virus-infected or fully vaccinated individuals. The receptor binding domain (RBD) of the virus spike protein reacts with host ACE2, leading to the entry of the virus into the cell. It is also the major antigenic site of the virus, with more than 90% of broadly neutralizing antibodies from either infected patients or vaccinated individuals targeting the spike RBD. Therefore, mutations in the RBD region are effective ways for SARS-CoV-2 variants to gain infectivity and escape the immunity built up by the original vaccines or infections. In this review, we focus on the impact of RBD mutations in SARS-CoV-2 variants of concern (VOC) and variants of interest (VOI) on ACE2 binding affinity and escape of serum antibody neutralization. We also provide protein structure models to show how the VOC and VOI RBD mutations affect ACE2 binding and allow escape of the virus from the therapeutic antibody, bamlanivimab.

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Molecular insights into receptor binding of recent emerging SARS-CoV-2 variants

Cited by 149 publications

References 55 publications

SARS-CoV-2 Outbreak on a Spanish Mink Farm: Epidemiological, Molecular, and Pathological Studies

SARS-CoV-2 Outbreak on a Spanish Mink Farm: Epidemiological, Molecular, and Pathological Studies

Interactions of SARS-CoV-2 protein E with cell junctions and polarity PDZ-containing proteins

SARS-CoV-2 Variants of Concern and Variants of Interest Receptor Binding Domain Mutations and Virus Infectivity

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