ACE2 glycans preferentially interact with SARS-CoV-2 over SARS-CoV

2021 ◽  
Author(s):  
Atanu Acharya ◽  
Diane L. Lynch ◽  
Anna Pavlova ◽  
Yui Tik Pang ◽  
James Gumbart
Keyword(s):  
Host Cell ◽  
Receptor Binding ◽  
Cell Receptor ◽  
Distinct Difference ◽  
S Protein ◽  
Binding Domains ◽  
Host Cell Receptor ◽  
Protein Receptor

We report a distinct difference in the interactions of the glycans of the host-cell receptor, ACE2, with SARS-CoV-2 and SARS-CoV S-protein receptor-binding domains (RBDs). Our analysis demonstrates that the ACE2...

scholarly journals ACE2 glycans preferentially interact with the RBD of SARS-CoV-2 over SARS-CoV

2021 ◽  
Author(s):  
Atanu Acharya ◽  
Diane Lynch ◽  
Anna Pavlova ◽  
Yui Tik Pang ◽  
James Gumbart
Keyword(s):  
Host Cell ◽  
Receptor Binding ◽  
Cell Receptor ◽  
Glycosylation Site ◽  
Distinct Difference ◽  
S Protein ◽  
Binding Domains ◽  
Host Cell Receptor ◽  
Protein Receptor

We report a distinct difference in the interactions of the glycans of the host-cell receptor, ACE2, with SARS-CoV-2 and SARS-CoV S-protein receptor-binding domains (RBDs). Our analysis demonstrates that the ACE2 glycan at N90 may offer protection against infections of both coronaviruses, while the ACE2 glycan at N322 enhances interactions with the SARS-CoV-2 RBD. The interactions of the ACE2 glycan at N322 with SARS-CoV RBD are blocked by the presence of the RBD glycan at N357 of the SARS-CoV RBD. The absence of this glycosylation site on SARS-CoV-2 RBD may enhance its binding with ACE2.

scholarly journals Role of Cysteines in Stabilizing the Randomized Receptor Binding Domains within Feline Leukemia Virus Envelope Proteins

2015 ◽  
Vol 90 (6) ◽  
pp. 2971-2980 ◽  
Author(s):  
Leonardo Valdivieso-Torres ◽  
Anindita Sarangi ◽  
Jillian Whidby ◽  
Joseph Marcotrigiano ◽  
Monica J. Roth
Keyword(s):  
Amino Acids ◽  
Host Cell ◽  
Receptor Binding ◽  
Disulfide Bonds ◽  
Cell Receptor ◽  
Envelope Proteins ◽  
Target Cells ◽  
Variable Regions ◽  
Binding Domains ◽  
Host Cell Receptor

ABSTRACTRetargeting of gammaretroviral envelope proteins has shown promising results in the isolation of novel isolates with therapeutic potential. However, the optimal conditions required to obtain high-affinity retargeted envelope proteins with narrow tropism are not understood. This study highlights the advantage of constrained peptides within receptor binding domains and validates the random library screening technique of obtaining novel retargeted Env proteins. Using a modified vector backbone to screen the envelope libraries on 143B osteosarcoma cells, three novel and unique retargeted envelopes were isolated. The use of complex disulfide bonds within variable regions required for receptor binding is found within natural gammaretroviral envelope isolates. Interestingly, two of the isolates, named AII and BV2, have a pair of cysteines located within the randomized region of 11 amino acids similar to that identified within the CP Env, an isolate identified in a previous Env library screen on the human renal carcinoma Caki-1 cell line. The amino acids within the randomized region of AII and BV2 envelopes that are essential for viral infection have been identified in this study and include these cysteine residues. Through mutagenesis studies, the putative disulfide bond pairs including and beyond the randomized region were examined. In parallel, the disulfide bonds of CP Env were identified using mass spectrometry. The results indicate that this pair of cysteines creates the structural context to position key hydrophobic (F and W) and basic (K and H) residues critical for viral titer and suggest that AII, BV2, and CP internal cysteines bond together in distinct ways.IMPORTANCERetargeted gammaretroviral particles have broad applications for therapeutic use. Although great advances have been achieved in identifying new Env-host cell receptor pairs, the rules for designing optimal Env libraries are still unclear. We have found that isolates with an additional pair of cysteines within the randomized region have the highest transduction efficiencies. This emphasizes the importance of considering cysteine pairs in the design of new libraries. Furthermore, our data clearly indicate that these cysteines are essential for viral infectivity by presenting essential residues to the host cell receptor. These studies facilitate the screening of Env libraries for functional entry into target cells, allowing the identification of novel gammaretroviral Envs targeting alternative host cell receptors for gene and protein delivery.

scholarly journals Mutations in two SARS-CoV-2 variants of concern reflect two distinct strategies of antibody escape

2021 ◽  
Author(s):  
Sebastian Fiedler ◽  
Viola Denninger ◽  
Alexey S. Morgunov ◽  
Alison Ilsley ◽  
Roland Worth ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Cell Receptor ◽  
Converting Enzyme ◽  
Wild Type ◽  
Angiotensin Converting Enzyme 2 ◽  
Binding Domains ◽  
Host Cell Receptor

Understanding the factors that contribute to antibody escape of SARS-CoV-2 and its variants is key for the development of drugs and vaccines that provide broad protection against a variety of virus variants. Using microfluidic diffusional sizing, we determined the dissociation constant ((KD)) for the interaction between receptor binding domains (RBDs) of SARS-CoV-2 in its original version (WT) as well as alpha and beta variants with the host-cell receptor angiotensin converting enzyme 2 (ACE2). For RBD-alpha, the ACE2-binding affinity was increased by a factor of ten when compared with RBD-WT, while ACE2-binding of RBD-beta was largely unaffected. However, when challenged with a neutralizing antibody that binds to both RBD-WT and RBD-alpha with low nanomolar (KD) values, RBD-beta displayed no binding, suggesting a substantial epitope change. In SARS-CoV-2 convalescent sera, RBD-binding antibodies showed low nanomolar affinities to both wild-type and variant RBD proteins—strikingly, the concentration of antibodies binding to RBD-beta was half that of RBD-WT and RBD-alpha, again indicating considerable epitope changes in the beta variant. Our data therefore suggests that one factor contributing to the higher transmissibility and antibody evasion of SARS-CoV-2 alpha and beta is a larger fraction of viruses that can form a complex with ACE2. However, the two variants employ different mechanisms to achieve this goal. While SARS-CoV-2 alpha RBD binds with greater affinity to ACE2 and is thus more difficult to displace from the receptor by neutralizing antibodies, RBD-beta is less accessible to antibodies due to epitope changes which increases the chances of ACE2-binding and infection.

scholarly journals Differential Antibody Recognition by Novel SARS-CoV-2 and SARS-CoV Spike Protein Receptor Binding Domains: Mechanistic Insights and Implications for the Design of Diagnostics and Therapeutics

2020 ◽  
Author(s):  
Ilda D’Annessa ◽  
Filippo Marchetti ◽  
Giorgio Colombo
Keyword(s):  
Receptor Binding ◽  
Viral Entry ◽  
Cell Receptor ◽  
Host Cells ◽  
Homologous Proteins ◽  
Protein Protein Interaction ◽  
Antibody Recognition ◽  
Binding Domains ◽  
Protein Receptor ◽  
Interaction Regions

AbstractThe appearance of the novel betacoronavirus SARS-CoV-2 represents a major threat to human health, and its diffusion around the world is causing dramatic consequences. The knowledge of the 3D structures of SARS-CoV-2 proteins can facilitate the development of therapeutic and diagnostic molecules. Specifically, comparative analyses of the structures of SARS-CoV-2 proteins and homologous proteins from previously characterized viruses, such as SARS-CoV, can reveal the common and/or distinctive traits that underlie the mechanisms of recognition of cell receptors and of molecules of the immune system.Herein, we apply our recently developed energy-based methods for the prediction of antibody-binding epitopes and protein-protein interaction regions to the Receptor Binding Domain (RBD) of the Spike proteins from SARS-CoV-2 and SARS-CoV. Our analysis focusses only on the study of the structure of RBDs in isolation, without making use of any previous knowledge of binding properties. Importantly, our results highlight structural and sequence differences among the regions that are predicted to be immunoreactive and bind/elicit antibodies. These results provide a rational basis to the observation that several SARS-CoV RDB-specific monoclonal antibodies fail to appreciably bind the SARS-CoV-2 counterpart. Furthermore, we correctly identify the region of SARS-CoV-2 RBD that is engaged by the cell receptor ACE2 during viral entry into host cells.The data, sequences and structures we present here can be useful for the development of novel therapeutic and diagnostic interventions.

scholarly journals The utility of native MS for understanding the mechanism of action of repurposed therapeutics in COVID-19: heparin as a disruptor of the SARS-CoV-2 interaction with its host cell receptor

2020 ◽  
Author(s):  
Yang Yang ◽  
Yi Du ◽  
Igor A. Kaltashov
Keyword(s):  
Host Cell ◽  
Gas Phase ◽  
Viral Entry ◽  
Protein A ◽  
Cell Receptor ◽  
Critical Element ◽  
S Protein ◽  
Host Cell Receptor ◽  
Native Ms ◽  
Gas Phase Ion

ABSTRACTThe emergence and rapid proliferation of the novel coronavirus (SARS-CoV-2) resulted in a global pandemic, with over six million cases and nearly four hundred thousand deaths reported world-wide by the end of May 2020. A rush to find the cures prompted re-evaluation of a range of existing therapeutics vis-à-vis their potential role in treating COVID-19, placing a premium on analytical tools capable of supporting such efforts. Native mass spectrometry (MS) has long been a tool of choice in supporting the mechanistic studies of drug/therapeutic target interactions, but its applications remain limited in the cases that involve systems with a high level of structural heterogeneity. Both SARS-CoV-2 spike protein (S-protein), a critical element of the viral entry to the host cell, and ACE2, its docking site on the host cell surface, are extensively glycosylated, making them challenging targets for native MS. However, supplementing native MS with a gas-phase ion manipulation technique (limited charge reduction) allows meaningful information to be obtained on the non-covalent complexes formed by ACE2 and the receptor-binding domain (RBD) of the S-protein. Using this technique in combination with molecular modeling also allows the role of heparin in destabilizing the ACE2/RBD association to be studied, providing critical information for understanding the molecular mechanism of its interference with the virus docking to the host cell receptor. Both short (pentasaccharide) and relatively long (eicosasaccharide) heparin oligomers form 1:1 complexes with RBD, indicating the presence of a single binding site. This association alters the protein conformation (to maximize the contiguous patch of the positive charge on the RBD surface), resulting in a notable decrease of its ability to associate with ACE2. The destabilizing effect of heparin is more pronounced in the case of the longer chains due to the electrostatic repulsion between the low-pI ACE2 and the heparin segments not accommodated on the RBD surface. In addition to providing important mechanistic information on attenuation of the ACE2/RBD association by heparin, the study demonstrates the yet untapped potential of native MS coupled to gas-phase ion chemistry as a means of facilitating rational repurposing of the existing medicines for treating COVID-19.Abstract Figure

Role of bacteriophage SPP1 tail spike protein gp21 on host cell receptor binding and trigger of phage DNA ejection

2011 ◽  
Vol 83 (2) ◽  
pp. 289-303 ◽  
Author(s):  
Inês Vinga ◽  
Catarina Baptista ◽  
Isabelle Auzat ◽  
Isabelle Petipas ◽  
Rudi Lurz ◽  
...  
Keyword(s):  
Host Cell ◽  
Receptor Binding ◽  
Cell Receptor ◽  
Spike Protein ◽  
Host Cell Receptor ◽  
Dna Ejection ◽  
Phage Dna ◽  
Tail Spike

scholarly journals Host Cell Receptor Binding by Baculovirus GP64 and Kinetics of Virion Entry

Virology ◽  
1999 ◽  
Vol 258 (2) ◽  
pp. 455-468 ◽  
Author(s):  
K.L. Hefferon ◽  
A.G.P. Oomens ◽  
S.A. Monsma ◽  
C.M. Finnerty ◽  
G.W. Blissard
Keyword(s):  
Host Cell ◽  
Receptor Binding ◽  
Cell Receptor ◽  
Host Cell Receptor ◽  
Kinetics Of

scholarly journals SARS-CoV-2, Early Entry Events

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
James P. Chambers ◽  
Jieh Yu ◽  
James J. Valdes ◽  
Bernard P. Arulanandam
Keyword(s):  
Host Cell ◽  
Receptor Binding ◽  
Conformational Changes ◽  
Cell Types ◽  
Proteolytic Processing ◽  
Binding Motif ◽  
Susceptible Host ◽  
S Protein ◽  
Protein Receptor ◽  
Specific Protease

Viruses are obligate intracellular parasites, and host cell entry is the first step in the viral life cycle. The SARS-CoV-2 (COVID-19) entry process into susceptible host tissue cells is complex requiring (1) attachment of the virus via the conserved spike (S) protein receptor-binding motif (RBM) to the host cell angiotensin-converting-enzyme 2 (ACE2) receptor, (2) S protein proteolytic processing, and (3) membrane fusion. Spike protein processing occurs at two cleavage sites, i.e., S1/S2 and S 2 ′ . Cleavage at the S1/S2 and S 2 ′ sites ultimately gives rise to generation of competent fusion elements important in the merging of the host cell and viral membranes. Following cleavage, shedding of the S1 crown results in significant conformational changes and fusion peptide repositioning for target membrane insertion and fusion. Identification of specific protease involvement has been difficult due to the many cell types used and studied. However, it appears that S protein proteolytic cleavage is dependent on (1) furin and (2) serine protease transmembrane protease serine 2 proteases acting in tandem. Although at present not clear, increased SARS-CoV-2 S receptor-binding motif binding affinity and replication efficiency may in part account for observed differences in infectivity. Cleavage of the ACE2 receptor appears to be yet another layer of complexity in addition to forfeiture and/or alteration of ACE2 function which plays an important role in cardiovascular and immune function.

Sign in / Sign up

Export Citation Format

Share Document