SARS-CoV-2 Spike receptor-binding domain with a G485R mutation in complex with human ACE2

Weekley, Claire M.; Purcell, Dfj; Parker, Michael W.

doi:10.1101/2021.03.16.434488

Cited by 4 publications

(6 citation statements)

References 20 publications

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“…Notably, even the most recent published experimental structures of the ACE2-spike interaction (Xiao et al, 2021) describe only small monosaccharides positioned at the putative sites of N-glycan binding, or are restricted only to the glycosylated RBD subdomain (Weekley et al, 2021). The present results should be taken as indicative of a generic system response, the atomic-scale details of the interactions being not yet comparable to any experimental data.…”

Section: On the Binding Of The Angiotensin Converting Enzyme-2 Receptor To S1-receptor-binding Subdomain Subdomainmentioning

confidence: 55%

DNA Aptamers Block the Receptor Binding Domain at the Spike Protein of SARS-CoV-2

Cleri

Lensink

Blossey

2021

Front. Mol. Biosci.

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DNA aptamers are versatile molecular species obtained by the folding of short single-stranded nucleotide sequences, with highly specific recognition capabilities against proteins. Here we test the ability of DNA aptamers to interact with the spike (S-)protein of the SARS-CoV-2 viral capsid. The S-protein, a trimer made up of several subdomains, develops the crucial function of recognizing the ACE2 receptors on the surface of human cells, and subsequent fusioning of the virus membrane with the host cell membrane. In order to achieve this, the S1 domain of one protomer switches between a closed conformation, in which the binding site is inaccessible to the cell receptors, and an open conformation, in which ACE2 can bind, thereby initiating the entry process of the viral genetic material in the host cell. Here we show, by means of state-of-the-art molecular simulations, that small DNA aptamers experimentally identified can recognize the S-protein of SARS-CoV-2, and characterize the details of the binding process. We find that their interaction with different subdomains of the S-protein can effectively block, or at least considerably slow down the opening process of the S1 domain, thereby significantly reducing the probability of virus-cell binding. We provide evidence that, as a consequence, binding of the human ACE2 receptor may be crucially affected under such conditions. Given the facility and low cost of fabrication of specific aptamers, the present findings could open the way to both an innovative viral screening technique with sub-nanomolar sensitivity, and to an effective and low impact curative strategy.

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Section: On the Binding Of The Angiotensin Converting Enzyme-2 Receptor To S1-receptor-binding Subdomain Subdomainmentioning

confidence: 55%

DNA Aptamers Block the Receptor Binding Domain at the Spike Protein of SARS-CoV-2

Cleri

Lensink

Blossey

2021

Front. Mol. Biosci.

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“…( B-E ) Properties of the ACE2 615 LFMYQY2HA–RBD interface. ( B ) Comparison of the buried-surface-area (BSA) of individual ACE2 residues involved in RBD binding between ACE2 615 LFMYQY2HA, ACE2 wild type (6M0J ( 37 ), 6VW1 ( 38 ), 7LO4 ( 85 ), 7NXC ( 86 )), or ACE2 with RBD enhancing mutations as reported by others (7DMU) ( 28 ). BSA values were calculated by PISA ( 72 ).…”

Section: Resultsmentioning

confidence: 99%

Engineered ACE2-Fc counters murine lethal SARS-CoV-2 infection through direct neutralization and Fc-effector activities

Chen

Sun

Ullah

et al. 2021

Preprint

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Soluble Angiotensin-Converting Enzyme 2 (ACE2) constitutes an attractive antiviral capable of targeting a wide range of coronaviruses utilizing ACE2 as their receptor. Here, using structure-guided approaches, we developed divalent ACE2 molecules by grafting the extracellular ACE2-domain onto a human IgG1 or IgG3 (ACE2-Fc). These ACE2-Fcs harbor structurally validated mutations that enhance spike (S) binding and remove angiotensin enzymatic activity. The lead variant bound tightly to S, mediated in vitro neutralization of SARS-CoV-2 variants of concern (VOCs) with sub-nanomolar IC50 and was capable of robust Fc-effector functions, including antibody-dependent-cellular cytotoxicity, phagocytosis and complement deposition. When tested in a stringent K18-hACE2 mouse model, it delayed death or effectively resolved lethal SARS-CoV-2 infection in a prophylactic or therapeutic setting utilizing the combined effect of neutralization and Fc-effector functions. These data confirm the utility of ACE2-Fcs as valuable agents in preventing and eliminating SARS-CoV-2 infection and demonstrate that ACE2-Fc therapeutic activity require Fc-effector functions.

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“…The main goal of determining the structure of a focused RBD without mutations is to understand the behaviour of the wild-type strain and to describe the main interactions of the S protein with hACE2 [ 43 ]. When introducing mutations or studying different strains, the goal may be to obtain new therapeutic agents based on either hACE2 or S protein, and to understand why new strains behave differently [ 23 , 24 , 41 , 47 ].…”

Section: Discussionmentioning

confidence: 99%

“…In the structure with mutation G485R (PDB 7LO4), residue 485, mutating from glycine to arginine, is not directly involved in the hACE2-SARS-CoV-2 S protein interaction, but close to Ab binding epitopes and in a loop region that makes multiple contacts with hACE2. This mutation leads to a rotation in the loop, affecting some interacting residues without significantly reducing the affinity [ 47 ]. Nevertheless, the conformational changes in the loop correlate with previous evidence that this mutation plays a role in antigenic escape from neutralising Abs, disrupting interactions involving E484 and F486 ( Figure 8 ) [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

“…This mutation leads to a rotation in the loop, affecting some interacting residues without significantly reducing the affinity [ 47 ]. Nevertheless, the conformational changes in the loop correlate with previous evidence that this mutation plays a role in antigenic escape from neutralising Abs, disrupting interactions involving E484 and F486 ( Figure 8 ) [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

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SARS-CoV-2 Virus−Host Interaction: Currently Available Structures and Implications of Variant Emergence on Infectivity and Immune Response

Queirós-Reis

Silva

Gonçalves

et al. 2021

IJMS

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Coronavirus disease 19, or COVID-19, is an infection associated with an unprecedented worldwide pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which has led to more than 215 million infected people and more than 4.5 million deaths worldwide. SARS-CoV-2 cell infection is initiated by a densely glycosylated spike (S) protein, a fusion protein, binding human angiotensin converting enzyme 2 (hACE2), that acts as the functional receptor through the receptor binding domain (RBD). In this article, the interaction of hACE2 with the RBD and how fusion is initiated after recognition are explored, as well as how mutations influence infectivity and immune response. Thus, we focused on all structures available in the Protein Data Bank for the interaction between SARS-CoV-2 S protein and hACE2. Specifically, the Delta variant carries particular mutations associated with increased viral fitness through decreased antibody binding, increased RBD affinity and altered protein dynamics. Combining both existing mutations and mutagenesis studies, new potential SARS-CoV-2 variants, harboring advantageous S protein mutations, may be predicted. These include mutations S13I and W152C, decreasing antibody binding, N460K, increasing RDB affinity, or Q498R, positively affecting both properties.

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SARS-CoV-2 Spike receptor-binding domain with a G485R mutation in complex with human ACE2

Cited by 4 publications

References 20 publications

DNA Aptamers Block the Receptor Binding Domain at the Spike Protein of SARS-CoV-2

DNA Aptamers Block the Receptor Binding Domain at the Spike Protein of SARS-CoV-2

Engineered ACE2-Fc counters murine lethal SARS-CoV-2 infection through direct neutralization and Fc-effector activities

SARS-CoV-2 Virus−Host Interaction: Currently Available Structures and Implications of Variant Emergence on Infectivity and Immune Response

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