Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2

Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for severe acute respiratory syndrome–coronavirus (SARS-CoV) and the new coronavirus (SARS-CoV-2) that is causing the serious coronavirus disease 2019 (COVID-19) epidemic. Here, we present cryo–electron microscopy structures of full-length human ACE2 in the presence of the neutral amino acid transporter B0AT1 with or without the receptor binding domain (RBD) of the surface spike glycoprotein (S protein) of SARS-CoV-2, both at an overall resolution of 2.9 angstroms, with a local resolution of 3.5 angstroms at the ACE2-RBD interface. The ACE2-B0AT1 complex is assembled as a dimer of heterodimers, with the collectrin-like domain of ACE2 mediating homodimerization. The RBD is recognized by the extracellular peptidase domain of ACE2 mainly through polar residues. These findings provide important insights into the molecular basis for coronavirus recognition and infection.

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Structural basis for the recognition of the 2019-nCoV by human ACE2

10.1101/2020.02.19.956946 ◽

2020 ◽

Cited By ~ 46

Author(s):

Renhong Yan ◽

Yuanyuan Zhang ◽

Yingying Guo ◽

Lu Xia ◽

Qiang Zhou

Keyword(s):

Amino Acid ◽

Pairwise Comparison ◽

Full Length ◽

Structural Basis ◽

Cellular Receptor ◽

Receptor Binding Domain ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2 ◽

Neutral Amino Acid Transporter ◽

Extracellular Peptidase

AbstractAngiotensin-converting enzyme 2 (ACE2) has been suggested to be the cellular receptor for the new coronavirus (2019-nCoV) that is causing the coronavirus disease 2019 (COVID-19). Like other coronaviruses such as the SARS-CoV, the 2019-nCoV uses the receptor binding domain (RBD) of the surface spike glycoprotein (S protein) to engage ACE2. We most recently determined the structure of the full-length human ACE2 in complex with a neutral amino acid transporter B0AT1. Here we report the cryo-EM structure of the full-length human ACE2 bound to the RBD of the 2019-nCoV at an overall resolution of 2.9 Å in the presence of B0AT1. The local resolution at the ACE2-RBD interface is 3.5 Å, allowing analysis of the detailed interactions between the RBD and the receptor. Similar to that for the SARS-CoV, the RBD of the 2019-nCoV is recognized by the extracellular peptidase domain (PD) of ACE2 mainly through polar residues. Pairwise comparison reveals a number of variations that may determine the different affinities between ACE2 and the RBDs from these two related viruses.

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A collection of designed peptides to target SARS-Cov-2 – ACE2 interaction: PepI-Covid19 database

10.1101/2020.04.28.051789 ◽

2020 ◽

Author(s):

Ruben Molina ◽

Baldo Oliva ◽

Narcis Fernandez-Fuentes

Keyword(s):

Scientific Community ◽

Therapeutic Agents ◽

Spike Protein ◽

Structural Basis ◽

Cellular Receptor ◽

Receptor Binding Domain ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2 ◽

Potential Impact ◽

Novel Therapeutic

AbstractThe angiotensin-converting enzyme 2 is the cellular receptor used by SARS coronavirus SARS-CoV and SARS-CoV-2 to enter the cell. Both coronavirus use the receptor-binding domain (RBD) of their viral spike protein to interact with ACE2. The structural basis of these interactions are already known, forming a dimer of ACE2 with a trimer of the spike protein, opening the door to target them to prevent the infection. Here we present PepI-Cov19 database, a repository of peptides designed to target the interaction between the RDB of SARS-CoV-2 and ACE2 as well as the dimerization of ACE2 monomers. The peptides were modelled using our method PiPreD that uses native elements of the interaction between the targeted protein and cognate partner that are subsequently included in the designed peptides. These peptides recapitulate stretches of residues present in the native interface plus novel and highly diverse conformations that preserve the key interactions on the interface. PepI-Covid19 database provides an easy and convenient access to this wealth of information to the scientific community with the view of maximizing its potential impact in the development of novel therapeutic agents.

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Structure of dimeric full-length human ACE2 in complex with B0AT1

10.1101/2020.02.17.951848 ◽

2020 ◽

Cited By ~ 18

Author(s):

Renhong Yan ◽

Yuanyuan Zhang ◽

Yaning Li ◽

Lu Xia ◽

Qiang Zhou

Keyword(s):

Amino Acid ◽

Molecular Basis ◽

Surface Expression ◽

Full Length ◽

Intestinal Cells ◽

Structural Modelling ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2 ◽

Neutral Amino Acid Transporter ◽

Surface Receptor

AbstractAngiotensin-converting enzyme 2 (ACE2) is the surface receptor for SARS coronavirus (SARS-CoV), directly interacting with the spike glycoprotein (S protein). ACE2 is also suggested to be the receptor for the new coronavirus (2019-nCoV), which is causing a serious epidemic in China manifested with severe respiratory syndrome. B0AT1 (SLC6A19) is a neutral amino acid transporter whose surface expression in intestinal cells requires ACE2. Here we present the 2.9 Å resolution cryo-EM structure of full-length human ACE2 in complex with B0AT1. The complex, assembled as a dimer of ACE2-B0AT1 heterodimers, exhibits open and closed conformations due to the shifts of the peptidase domains (PDs) of ACE2. A newly resolved Collectrin-like domain (CLD) on ACE2 mediates homo-dimerization. Structural modelling suggests that the ACE2-B0AT1 complex can bind two S proteins simultaneously, providing important clues to the molecular basis for coronavirus recognition and infection.

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Possible Transmission Flow of SARS-CoV-2 Based on ACE2 Features

Molecules ◽

10.3390/molecules25245906 ◽

2020 ◽

Vol 25 (24) ◽

pp. 5906

Author(s):

Sk. Sarif Hassan ◽

Shinjini Ghosh ◽

Diksha Attrish ◽

Pabitra Pal Choudhury ◽

Alaa A. A. Aljabali ◽

...

Keyword(s):

Amino Acids ◽

Severe Acute Respiratory Syndrome ◽

Angiotensin Converting Enzyme ◽

Receptor Binding ◽

Comprehensive Analysis ◽

Cellular Receptor ◽

Receptor Binding Domain ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2 ◽

Protein Receptor

Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) that is engendering the severe coronavirus disease 2019 (COVID-19) pandemic. The spike (S) protein receptor-binding domain (RBD) of SARS-CoV-2 binds to the three sub-domains viz. amino acids (aa) 22–42, aa 79–84, and aa 330–393 of ACE2 on human cells to initiate entry. It was reported earlier that the receptor utilization capacity of ACE2 proteins from different species, such as cats, chimpanzees, dogs, and cattle, are different. A comprehensive analysis of ACE2 receptors of nineteen species was carried out in this study, and the findings propose a possible SARS-CoV-2 transmission flow across these nineteen species.

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S19W, T27W, and N330Y mutations in ACE2 enhance SARS-CoV-2 S-RBD binding toward both wild-type and antibody-resistant viruses and its molecular basis

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00756-4 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Fei Ye ◽

Xi Lin ◽

Zimin Chen ◽

Fanli Yang ◽

Sheng Lin ◽

...

Keyword(s):

Molecular Basis ◽

Structural Data ◽

Van Der Waals Interactions ◽

Side Chains ◽

Receptor Binding Domain ◽

Converting Enzyme ◽

Wild Type ◽

Angiotensin Converting Enzyme 2 ◽

Domain Protein ◽

Entry Inhibition

AbstractSARS-CoV-2 recognizes, via its spike receptor-binding domain (S-RBD), human angiotensin-converting enzyme 2 (ACE2) to initiate infection. Ecto-domain protein of ACE2 can therefore function as a decoy. Here we show that mutations of S19W, T27W, and N330Y in ACE2 could individually enhance SARS-CoV-2 S-RBD binding. Y330 could be synergistically combined with either W19 or W27, whereas W19 and W27 are mutually unbeneficial. The structures of SARS-CoV-2 S-RBD bound to the ACE2 mutants reveal that the enhanced binding is mainly contributed by the van der Waals interactions mediated by the aromatic side-chains from W19, W27, and Y330. While Y330 and W19/W27 are distantly located and devoid of any steric interference, W19 and W27 are shown to orient their side-chains toward each other and to cause steric conflicts, explaining their incompatibility. Finally, using pseudotyped SARS-CoV-2 viruses, we demonstrate that these residue substitutions are associated with dramatically improved entry-inhibition efficacy toward both wild-type and antibody-resistant viruses. Taken together, our biochemical and structural data have delineated the basis for the elevated S-RBD binding associated with S19W, T27W, and N330Y mutations in ACE2, paving the way for potential application of these mutants in clinical treatment of COVID-19.

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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

Biomedicines ◽

10.3390/biomedicines9081038 ◽

2021 ◽

Vol 9 (8) ◽

pp. 1038

Author(s):

Deborah Giordano ◽

Luigi De Masi ◽

Maria Antonia Argenio ◽

Angelo Facchiano

Keyword(s):

Angiotensin Converting Enzyme ◽

In Silico Analysis ◽

Host Cells ◽

Spike Protein ◽

Cellular Receptor ◽

Receptor Binding Domain ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2 ◽

The World ◽

Silico Analysis

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.

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Effective ACE2 Peptide-Nanoparticle Conjugation and Its Binding with SARS-Cov-2 RBD Quantified by Dynamic Light Scattering

Chemical Communications ◽

10.1039/d1cc02267a ◽

2021 ◽

Author(s):

Vince St. Dollente Mesias ◽

Hongni Zhu ◽

Xiao Tang ◽

Xin Dai ◽

Yusong Guo ◽

...

Keyword(s):

Light Scattering ◽

Dynamic Light Scattering ◽

Angiotensin Converting Enzyme ◽

Receptor Binding ◽

Spike Protein ◽

Cellular Receptor ◽

Receptor Binding Domain ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2 ◽

Protein Receptor

The infection of coronavirus initiates with the binding between its spike protein receptor binding domain (RBD) and a human cellular receptor called angiotensin-converting enzyme 2 (ACE2). Here, we construct truncated...

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The molecular basis for SARS-CoV-2 binding to dog ACE2

Nature Communications ◽

10.1038/s41467-021-24326-y ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Zengyuan Zhang ◽

Yanfang Zhang ◽

Kefang Liu ◽

Yan Li ◽

Qiong Lu ◽

...

Keyword(s):

Binding Affinity ◽

Molecular Basis ◽

Domestic Animals ◽

Receptor Binding Domain ◽

Salt Bridges ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2 ◽

Binding Interface ◽

Protein Receptor ◽

Contact Residues

AbstractSARS-CoV-2 can infect many domestic animals, including dogs. Herein, we show that dog angiotensin-converting enzyme 2 (dACE2) can bind to the SARS-CoV-2 spike (S) protein receptor binding domain (RBD), and that both pseudotyped and authentic SARS-CoV-2 can infect dACE2-expressing cells. We solved the crystal structure of RBD in complex with dACE2 and found that the total number of contact residues, contact atoms, hydrogen bonds and salt bridges at the binding interface in this complex are slightly fewer than those in the complex of the RBD and human ACE2 (hACE2). This result is consistent with the fact that the binding affinity of RBD to dACE2 is lower than that of hACE2. We further show that a few important mutations in the RBD binding interface play a pivotal role in the binding affinity of RBD to both dACE2 and hACE2. Our work reveals a molecular basis for cross-species transmission and potential animal spread of SARS-CoV-2, and provides new clues to block the potential transmission chains of this virus.

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A Bioluminescent Biosensor for Quantifying the Interaction of SARS-CoV-2 and Its Receptor ACE2 in Cells and In Vitro

Viruses ◽

10.3390/v13061055 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1055

Author(s):

Xiaolong Yang ◽

Lidong Liu ◽

Yawei Hao ◽

Eva So ◽

Sahar Sarmasti Emami ◽

...

Keyword(s):

Small Molecules ◽

Living Cells ◽

Cellular Receptor ◽

Receptor Binding Domain ◽

Converting Enzyme ◽

Discovery Process ◽

Drug Discovery Process ◽

Angiotensin Converting Enzyme 2 ◽

Host Interactions

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is currently spreading and mutating with increasing speed worldwide. Therefore, there is an urgent need for a simple, sensitive, and high-throughput (HTP) assay to quantify virus–host interactions in order to quickly evaluate the infectious ability of mutant viruses and to develop or validate virus-inhibiting drugs. Here, we developed an ultrasensitive bioluminescent biosensor to evaluate virus–cell interactions by quantifying the interaction between the SARS-CoV-2 receptor binding domain (RBD) and its cellular receptor angiotensin-converting enzyme 2 (ACE2) both in living cells and in vitro. We have successfully used this novel biosensor to analyze SARS-CoV-2 RBD mutants and evaluated candidate small molecules (SMs), antibodies, and peptides that may block RBD:ACE2 interaction. This simple, rapid, and HTP biosensor tool will significantly expedite the detection of viral mutants and the anti-COVID-19 drug discovery process.

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Possible transmission flow of SARS-CoV-2 based on ACE2 features

10.1101/2020.10.08.332452 ◽

2020 ◽

Author(s):

Sk. Sarif Hassan ◽

Shinjini Ghosh ◽

Diksha Attrish ◽

Pabitra Pal Choudhury ◽

Vladimir N. Uversky ◽

...

Keyword(s):

Amino Acids ◽

Severe Acute Respiratory Syndrome ◽

Angiotensin Converting Enzyme ◽

Receptor Binding ◽

Comprehensive Analysis ◽

Cellular Receptor ◽

Receptor Binding Domain ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2 ◽

Protein Receptor

AbstractAngiotensin-converting enzyme 2 (ACE2) is the cellular receptor for the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) that is engendering the severe coronavirus disease 2019 (COVID-19) pandemic. The spike (S) protein receptor-binding domain (RBD) of SARS-CoV-2 binds to the three sub-domains viz. amino acids (aa) 22-42, aa 79-84, and aa 330-393 of ACE2 on human cells to initiate entry. It was reported earlier that the receptor utilization capacity of ACE2 proteins from different species, such as cats, chimpanzees, dogs, and cattle, are different. A comprehensive analysis of ACE2 receptors of nineteen species was carried out in this study, and the findings propose a possible SARS-CoV-2 transmission flow across these nineteen species.

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