Structural Dissection of Viral Spike-Protein Binding of SARS-CoV-2 and SARS-CoV-1 to the Human Angiotensin-Converting Enzyme 2 (ACE2) as Cellular Receptor.

Deborah Giordano,Angelo Facchiano,Luigi De Masi,Maria Antonia Argenio

doi:10.3390/biomedicines9081038

Abstract

An outbreak by a new severe acute respiratory syndrome betacoronavirus (SARS-CoV-2) has spread CoronaVirus Disease 2019 (COVID-19) all over the world. Immediately, following studies have confirmed the human Angiotensin-Converting Enzyme 2 (ACE2) as a cellular receptor of viral Spike-Protein (Sp) that mediates the CoV-2 invasion into the pulmonary host cells. Here, we compared the molecular interactions of the viral Sp from previous SARS-CoV-1 of 2002 and SARS-CoV-2 with the host ACE2 protein by in silico analysis of the available experimental structures of Sp-ACE2 complexes. The K417 amino acid residue, located in the region of Sp Receptor-Binding Domain (RBD) of the new coronavirus SARS-CoV-2, showed to have a key role for the binding to the ACE2 N-terminal region. The R426 residue of SARS-CoV-1 Sp-RBD also plays a key role, although by interacting with the central region of the ACE2 sequence. Therefore, our study evidenced peculiarities in the interactions of the two Sp-ACE2 complexes. Our outcomes were consistent with previously reported mutagenesis studies on SARS-CoV-1 and support the idea that a new and different RBD was acquired by SARS-CoV-2. These results have interesting implications and suggest further investigations.

Highlights

Published: 18 August 2021At the end of 2019, an epidemic cluster of unknown etiology causing interstitial bilateral pneumonia highly transmissible by human-to-human first emerged in the city ofWuhan, Hubei province, China [1,2,3]
To understand the specific molecular interactions underlying the binding of Sp to Angiotensin-Converting Enzyme 2 (ACE2), we investigated in silico the X-ray crystallographic structures, available in the public domain Protein Data Bank (PDB), of human ACE2 in complex with SARS-CoV-2/CoV-1 Sp, by analyzing in detail the interacting amino acids at the chain-chain interfaces
The molecular interactions in the Sp-ACE2 complex are of crucial importance for the successful coronavirus attack, and their complete understanding can be useful for the definition of the mechanism of action as well as for ascertaining possible interaction differences in the case of Sp variants

Summary

Introduction

Published: 18 August 2021At the end of 2019, an epidemic cluster of unknown etiology causing interstitial bilateral pneumonia highly transmissible by human-to-human first emerged in the city ofWuhan, Hubei province, China [1,2,3]. The etiologic agent was identified as a not known before positive-strand RNA betacoronavirus (CoV-2) by the Coronaviridae Study Group (CSG) of the International Committee on Taxonomy of Viruses Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the seventh coronavirus known to infect humans, closely related to SARS-CoV-1 of 2002 with 79.5% sequence identity of probable zoonotic origin based on phylogeny, taxonomy and established practices [4,5,6,7]. Human-to-human contacts have rapidly increased the spread of the new disease, named the 2019 CoronaVirus Disease (COVID-19), mainly transmitted by respiratory bioaerosols (Flügge’s droplets), fomites and close contacts [8]. There is evidence of asymptomatic and paucisymptomatic patients, forming the main infection reservoirs, severe cases of COVID-19 can evolve towards a lethal respiratory syndrome (i.e., SARS)

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