Conformational dynamics of SARS-CoV-2 trimeric spike glycoprotein in complex with receptor ACE2 revealed by cryo-EM

Xu, Cong; Wang, Yanxing; Liu, Caixuan; Zhang, Chao; Han, Wenyu; Hong, Xiaoyu; Wang, Yifan; Qin, Hong; Wang, Shutian; Qi-guo, Zhao; Wang, Yalei; Yang, Yong; Chen, Kaijian; Zheng, Wei; Kong, Liangliang; Wang, Fangfang; Zuo, Qinyu; Huang, Zhong; Yao, Cong

doi:10.1126/sciadv.abe5575

Cited by 329 publications

(387 citation statements)

References 72 publications

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“…The No-Linker and 5 aa S-Linker systems had similar high peaks of flexibility in their amino acids (Figure 2b). Residues T470-F490 and Q498-Y505, which are suggested to bind with the ACE2 receptor [34][35][36], demonstrated a higher flexibility. Moreover, after correlating these RMSF findings with the RMSD data, the 13 aa L-Linker system had less flexible spike RBD monomers, which gives a clue that there might have been a higher number of intermolecular interactions between the neighboring spike RBD monomers (Figure 2b).…”

Section: Resultsmentioning

confidence: 99%

“…These findings correlated with our previous data [35] and other recent studies [3,34,39,54] that showed the spike RBD domains could have two "up" and "down" conformations, which are ACE2-receptor accessible and ACE2-receptor inaccessible states, respectively. [34][35][36]. (c)The conformations detected for the SARS-CoV-2 spike RBD-H_ferritin complexes, with different chimeric constructs varying in the length of the linker (No-Linker, 5 aa S-Linker, and 13 aa L-Linker).…”

Section: Resultsmentioning

confidence: 99%

“…We also compared the difference in dynamics between two different ferritins when they carried the same antigen molecules (spike RBD domain). In addition, the behavior of the spike RBD regions (470TEIYQAGSTPCNGVEGFNCYF490 and 498QPTNGVGY505 [34][35][36]) responsible for interacting with the host ACE2 receptor was explicitly evaluated. To our knowledge, this is the first comprehensive computational study showing the dynamics of ferritin-RBD constructs in detail, which might have an impact on future vaccine development against SARS-CoV-2 and/or related coronaviruses.…”

Section: Introductionmentioning

confidence: 99%

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Multivalent Display of SARS-CoV-2 Spike (RBD Domain) of COVID-19 to Nanomaterial, Protein Ferritin Nanocages

et al. 2021

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SARS-CoV-2, or COVID-19, has a devastating effect on our society, both in terms of quality of life and death rates; hence, there is an urgent need for developing safe and effective therapeutics against SARS-CoV-2. The most promising strategy to fight against this deadly virus is to develop an effective vaccine. Internalization of SARS-CoV-2 into the human host cell mainly occurs through the binding of the coronavirus spike protein (a trimeric surface glycoprotein) to the human angiotensin-converting enzyme 2 (ACE2) receptor. The spike-ACE2 protein–protein interaction is mediated through the receptor-binding domain (RBD) of the spike protein. Mutations in the spike RBD can significantly alter interactions with the ACE2 host receptor. Due to its important role in virus transmission, the spike RBD is considered to be one of the key molecular targets for vaccine development. In this study, a spike RBD-based subunit vaccine was designed by utilizing a ferritin protein nanocage as a scaffold. Several fusion protein constructs were designed in silico by connecting the spike RBD via a synthetic linker (different sizes) to different ferritin subunits (H-ferritin and L-ferritin). The stability and the dynamics of the engineered nanocage constructs were tested by extensive molecular dynamics simulation (MDS). Based on our MDS analysis, a five amino acid-based short linker (S-Linker) was the most effective for displaying the spike RBD over the surface of ferritin. The behavior of the spike RBD binding regions from the designed chimeric nanocages with the ACE2 receptor was highlighted. These data propose an effective multivalent synthetic nanocage, which might form the basis for new vaccine therapeutics designed against viruses such as SARS-CoV-2.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Multivalent Display of SARS-CoV-2 Spike (RBD Domain) of COVID-19 to Nanomaterial, Protein Ferritin Nanocages

et al. 2021

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“…Conflicts between the data sets were mostly confined to a small number of RBD residues that are buried in the major prefusion conformation of S yet are exposed when the isolated RBD is expressed on yeast, as well as higher mutational tolerance for receptor binding in the human cell data set, possibly due to differences in avid binding of dimeric ACE2 receptors between the two systems. Both studies ignore mutations in the viral spike outside the RBD that may influence escape from antibodies or modulate receptor binding through allostery or epistasis, for example, by increasing dynamic exposure of the RBD for receptor recognition as occurs in the D614G virus variant (Ozono et al, 2021;Xu et al, 2021). Future work should be dedicated toward understanding the mutational landscape of the entire S glycoprotein for folding/expression, ACE2 binding, infectivity, and interactions with monoclonal antibodies targeting domains other than the RBD.…”

Section: Selection Strategies For Understanding Sequence Diversity and Evolution Of Viral Glycoproteinsmentioning

confidence: 99%

Deep Mutational Scanning of Viral Glycoproteins and Their Host Receptors

Narayanan

Procko

2021

Front. Mol. Biosci.

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Deep mutational scanning or deep mutagenesis is a powerful tool for understanding the sequence diversity available to viruses for adaptation in a laboratory setting. It generally involves tracking an in vitro selection of protein sequence variants with deep sequencing to map mutational effects based on changes in sequence abundance. Coupled with any of a number of selection strategies, deep mutagenesis can explore the mutational diversity available to viral glycoproteins, which mediate critical roles in cell entry and are exposed to the humoral arm of the host immune response. Mutational landscapes of viral glycoproteins for host cell attachment and membrane fusion reveal extensive epistasis and potential escape mutations to neutralizing antibodies or other therapeutics, as well as aiding in the design of optimized immunogens for eliciting broadly protective immunity. While less explored, deep mutational scans of host receptors further assist in understanding virus-host protein interactions. Critical residues on the host receptors for engaging with viral spikes are readily identified and may help with structural modeling. Furthermore, mutations may be found for engineering soluble decoy receptors as neutralizing agents that specifically bind viral targets with tight affinity and limited potential for viral escape. By untangling the complexities of how sequence contributes to viral glycoprotein and host receptor interactions, deep mutational scanning is impacting ideas and strategies at multiple levels for combatting circulating and emergent virus strains.

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“…United Kingdom is facing more than a thousand deaths in a single day and the new variant is more transmissible than the previous virus. I have been analyzing a recently published structure of SARS-CoV-2 spike bound to ACE2 receptor (PDB 7DF4, Xu et al 2020) and found why the new variants are more transmissible. These findings have been obtained using UCSF Chimera software and molecular dynamics simulations (NAMD and VMD) in a supercomputer Frontera from TACC (Texas Advanced Computing Center).…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 Structural Analysis of Receptor Binding Domain New Variants from United Kingdom and South Africa

Padilla-Sanchez¹

2021

RIO

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SARS-CoV-2 has caused more than 80 million infections and close to 2 million deaths worldwide as of January 2021. This pandemic has caused an incredible damage to humanity being it medically and/or financially halting life as we know it. If it were not enough, the current virus is changing to a more deadly form because of the mutations that are arising on its genome. Importantly, two variants have emerged in recent months, one in United Kingdom and the other in South Africa that are more infectious and escape antibody binding. These two variants have mutations in the receptor binding domain of the spike glycoprotein namely N501Y (UK, SA), K417N (SA) and E484K (SA). Here, I present a structural analysis of spike glycoprotein bound to ACE2 (angiotensin converting enzyme 2) where the mutations have been introduced in silico showing the reason why these variants bind better to ACE2 receptors.

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Conformational dynamics of SARS-CoV-2 trimeric spike glycoprotein in complex with receptor ACE2 revealed by cryo-EM

Cited by 329 publications

References 72 publications

Multivalent Display of SARS-CoV-2 Spike (RBD Domain) of COVID-19 to Nanomaterial, Protein Ferritin Nanocages

Multivalent Display of SARS-CoV-2 Spike (RBD Domain) of COVID-19 to Nanomaterial, Protein Ferritin Nanocages

Deep Mutational Scanning of Viral Glycoproteins and Their Host Receptors

SARS-CoV-2 Structural Analysis of Receptor Binding Domain New Variants from United Kingdom and South Africa

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