Crystal structure of the post-fusion core of the Human coronavirus 229E spike protein at 1.86 Å resolution

Human coronavirus 229E (HCoV-229E) usually causes mild upper respiratory infections in heathy adults, but may lead to severe complications or mortality in individuals with weakened immune systems. Virus entry of HCoV-229E is mediated by its spike (S) protein, where the S1 domain facilitates attachment to host cells and the S2 domain is involved in subsequent fusion of the virus and host membranes. During the fusion process, two heptad repeats, HR1 and HR2, in the S2 domain assemble into a six-helix membrane-fusion structure termed the fusion core. Here, the complete fusion-core structure of HCoV-229E has been determined at 1.86 Å resolution, representing the most complete post-fusion conformation thus far among published human alphacoronavirus (α-HCoV) fusion-core structures. The overall structure of the HCoV-229E fusion core is similar to those of SARS, MERS and HCoV-NL63, but the packing of its 3HR1 core differs from those of SARS and MERS in that it contains more noncanonical `x' and `da' layers. Side-by-side electrostatic surface comparisons reveal that the electrostatic surface potentials are opposite in α-HCoVs and β-HCoVs at certain positions and that the HCoV-229E surface also appears to be the most hydrophobic among the various HCoVs. In addition to the highly conserved hydrophobic interactions between HR1 and HR2, some polar and electrostatic interactions are also well preserved across different HCoVs. This study adds to the structural profiling of HCoVs to aid in the structure-based design of pan-coronavirus small molecules or peptides to inhibit viral fusion.

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Fatal Pneumonia Associated With a Novel Genotype of Human Coronavirus OC43

Frontiers in Microbiology ◽

10.3389/fmicb.2021.795449 ◽

2022 ◽

Vol 12 ◽

Author(s):

Susanna Kar Pui Lau ◽

Kenneth Sze Ming Li ◽

Xin Li ◽

Ka-Yan Tsang ◽

Siddharth Sridhar ◽

...

Keyword(s):

Genetic Distance ◽

Respiratory Infections ◽

Endotracheal Aspirate ◽

Human Coronavirus ◽

Genotype I ◽

Viral Loads ◽

Pairwise Genetic Distance ◽

Distinct Cluster ◽

Upper Respiratory ◽

Novel Genotype

Since its first discovery in 1967, human coronavirus OC43 (HCoV-OC43) has been associated with mild self-limiting upper respiratory infections worldwide. Fatal primary pneumonia due to HCoV-OC43 is not frequently described. This study describes a case of fatal primary pneumonia associated with HCoV-OC43 in a 75-year-old patient with good past health. The viral loads of the respiratory tract specimens (bronchoalveolar lavage and endotracheal aspirate) from diagnosis to death were persistently high (3.49 × 106–1.10 × 1010 copies/ml). HCoV-OC43 at a 6.46 × 103 copies/ml level was also detected from his pleural fluid 2 days before his death. Complete genome sequencing and phylogenetic analysis showed that the present HCoV-OC43 forms a distinct cluster with three other HCoV-OC43 from United States, with a bootstrap value of 100% and sharing 99.9% nucleotide identities. Pairwise genetic distance between this cluster and other HCoV-OC43 genotypes ranged from 0.27 ± 0.02% to 1.25 ± 0.01%. In contrast, the lowest pairwise genetic distance between existing HCoV-OC43 genotypes was 0.26 ± 0.02%, suggesting that this cluster constitutes a novel HCoV-OC43 genotype, which we named genotype I. Unlike genotypes D, E, F, G, and H, no recombination event was observed for this novel genotype. Structural modeling revealed that the loop with the S1/S2 cleavage site was four amino acids longer than other HCoV-OC43, making it more exposed and accessible to protease, which may have resulted in its possible hypervirulence.

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Analysis of human coronavirus 229E spike and nucleoprotein genes demonstrates genetic drift between chronologically distinct strains

Journal of General Virology ◽

10.1099/vir.0.81662-0 ◽

2006 ◽

Vol 87 (5) ◽

pp. 1203-1208 ◽

Cited By ~ 32

Author(s):

Doris Chibo ◽

Chris Birch

Keyword(s):

Phylogenetic Analysis ◽

Respiratory Infections ◽

N Gene ◽

Human Coronavirus ◽

S Gene ◽

Limited Variation ◽

Contrast Analysis ◽

Human Coronaviruses ◽

Human Coronavirus 229E ◽

S Genes

Historically, coronaviruses have been recognized as a cause of minor respiratory infections in humans. However, the recent identification of three novel human coronaviruses, one causing severe acute respiratory syndrome (SARS), has prompted further examination of these viruses. Previous studies of geographically and chronologically distinct Human coronavirus 229E (HCoV-229E) isolates have found only limited variation within S gene nucleotide sequences. In contrast, analysis of the S genes of contemporary Human coronavirus OC43 variants identified in Belgium revealed two distinct viruses circulating during 2003 and 2004. Here, the S and N gene sequences of 25 HCoV-229E variants identified in Victoria, Australia, between 1979 and 2004 in patients with symptomatic infections were determined. Phylogenetic analysis showed clustering of the isolates into four groups, with evidence of increasing divergence with time. Evidence of positive selection in the S gene was also established.

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Flavonols and dihydroflavonols inhibit the main protease activity of SARS-CoV-2 and the replication of human coronavirus 229E

10.1101/2021.07.01.450756 ◽

2021 ◽

Author(s):

Yue Zhu ◽

Frank Scholle ◽

Samantha C. Kisthardt ◽

Deyu Xie

Keyword(s):

Docking Simulation ◽

Binding Pocket ◽

Developed Countries ◽

Host Cells ◽

Human Coronavirus ◽

Main Protease ◽

Ic50 Values ◽

In Vitro Inhibition ◽

Human Coronavirus 229E

Since December 2019, the deadly novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the current COVID-19 pandemic. To date, vaccines are available in the developed countries to prevent the infection of this virus, however, medicines are necessary to help control COVID-19. Human coronavirus 229E (HCoV-229E) causes the common cold. The main protease (Mpro) is an essential enzyme required for the multiplication of these two viruses in the host cells, and thus is an appropriate candidate to screen potential medicinal compounds. Flavonols and dihydroflavonols are two groups of plant flavonoids. In this study, we report docking simulation with two Mpro enzymes and five flavonols and three dihydroflavonols, in vitro inhibition of the SARS-CoV-2 Mpro, and in vitro inhibition of the HCoV 229E replication. The docking simulation results predicted that (+)-dihydrokaempferol, (+)-dihydroquercetin, (+)-dihydromyricetin, kaempferol, quercetin, myricentin, isoquercetin, and rutin could bind to at least two subsites (S1, S1', S2, and S4) in the binding pocket and inhibit the activity of SARS-CoV-2 Mpro. Their affinity scores ranged from -8.8 to -7.4. Likewise, these compounds were predicted to bind and inhibit the HCoV-229E Mpro activity with affinity scores ranging from -7.1 to -7.8. In vitro inhibition assays showed that seven available compounds effectively inhibited the SARS-CoV-2 Mpro activity and their IC50 values ranged from 0.125 to 12.9 uM. Five compounds inhibited the replication of HCoV-229E in Huh-7 cells. These findings indicate that these antioxidative flavonols and dihydroflavonols are promising candidates for curbing the two viruses.

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Non-RBM Mutations Impaired SARS-CoV-2 Spike Protein Regulated to the ACE2 Receptor Based on Molecular Dynamic Simulation

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.614443 ◽

2021 ◽

Vol 8 ◽

Author(s):

Yaoqiang Du ◽

Hao Wang ◽

Linjie Chen ◽

Quan Fang ◽

Biqin Zhang ◽

...

Keyword(s):

Free Energy ◽

Receptor Binding ◽

Electrostatic Interactions ◽

Hydrophobic Interactions ◽

Binding Free Energy ◽

Host Cells ◽

Dynamics Simulation ◽

Random Coil ◽

Binding Motif ◽

Binding Loop

The emergence of novel coronavirus mutants is a main factor behind the deterioration of the epidemic situation. Further studies into the pathogenicity of these mutants are thus urgently needed. Binding of the spinous protein receptor binding domain (RBD) of SARS-CoV-2 to the angiotensin-converting enzyme 2 (ACE2) receptor was shown to initiate coronavirus entry into host cells and lead to their infection. The receptor-binding motif (RBM, 438–506) is a region that directly interacts with ACE2 receptor in the RBD and plays a crucial role in determining affinity. To unravel how mutations in the non-RBM regions impact the interaction between RBD and ACE2, we selected three non-RBM mutant systems (N354D, D364Y, and V367F) from the documented clinical cases, and the Q498A mutant system located in the RBM region served as the control. Molecular dynamics simulation was conducted on the mutant systems and the wild-type (WT) system, and verified experiments also performed. Non-RBM mutations have been shown not only to change conformation of the RBM region but also to significantly influence its hydrogen bonding and hydrophobic interactions. In particular, the D364Y and V367F systems showed a higher affinity for ACE2 owing to their electrostatic interactions and polar solvation energy changes. In addition, although the binding free energy at this point increased after the mutation of N354D, the conformation of the random coil (Pro384-Asp389) was looser than that of other systems, and the combined effect weakened the binding free energy between RBD and ACE2. Interestingly, we also found a random coil (Ala475-Gly485). This random coil is very sensitive to mutations, and both types of mutations increase the binding free energy of residues in this region. We found that the binding loop (Tyr495-Tyr505) in the RBD domain strongly binds to Lys353, an important residue of the ACE2 domain previously identified. The binding free energy of the non-RBM mutant group at the binding loop had positive and negative changes, and these changes were more obvious than that of the Q498A system. The results of this study elucidate the effect of non-RBM mutation on ACE2-RBD binding, and provide new insights for SARS-CoV-2 mutation research.

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Lessons Learned From Serial Isolations Of Human Coronavirus 229E From Environmental Surfaces Of A Classroom During Influenza Season

10.31988/scitrends.16688 ◽

2018 ◽

Author(s):

John Lednicky

Keyword(s):

Influenza Season ◽

Lessons Learned ◽

Human Coronavirus ◽

Environmental Surfaces ◽

Human Coronavirus 229E

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Complement Inactivation Strategy of Staphylococcus aureus Using Decay-Accelerating Factor and the Response of Infected HaCaT Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22084015 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4015

Author(s):

Kyoung Ok Jang ◽

Youn Woo Lee ◽

Hangeun Kim ◽

Dae Kyun Chung

Keyword(s):

Staphylococcus Aureus ◽

Immune Cells ◽

Respiratory Infections ◽

Food Poisoning ◽

Surface Expression ◽

Host Cells ◽

Hacat Cells ◽

Decay Accelerating Factor ◽

Ligand Expression ◽

The Complement System

Staphylococcus aureus is a species of Gram-positive staphylococcus. It can cause sinusitis, respiratory infections, skin infections, and food poisoning. Recently, it was discovered that S. aureus infects epithelial cells, but the interaction between S. aureus and the host is not well known. In this study, we confirmed S. aureus to be internalized by HaCaT cells using the ESAT-6-like protein EsxB and amplified within the host over time by escaping host immunity. S. aureus increases the expression of decay-accelerating factor (CD55) on the surfaces of host cells, which inhibits the activation of the complement system. This mechanism makes it possible for S. aureus to survive in host cells. S. aureus, sufficiently amplified within the host, is released through the initiation of cell death. On the other hand, the infected host cells increase their surface expression of UL16 binding protein 1 to inform immune cells that they are infected and try to be eliminated. These host defense systems seem to involve the alteration of tight junctions and the induction of ligand expression to activate immune cells. Taken together, our study elucidates a novel aspect of the mechanisms of infection and immune system evasion for S. aureus.

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Targeting Viral Surface Proteins through Structure-Based Design

Viruses ◽

10.3390/v13071320 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1320

Author(s):

Yogesh B Narkhede ◽

Karen J Gonzalez ◽

Eva-Maria Strauch

Keyword(s):

Public Health ◽

Viral Infections ◽

Respiratory Viruses ◽

Surface Proteins ◽

Host Cells ◽

Viral Fusion ◽

Health It ◽

Viral Particles ◽

Pathogenic Viruses ◽

Viral Surface

The emergence of novel viral infections of zoonotic origin and mutations of existing human pathogenic viruses represent a serious concern for public health. It warrants the establishment of better interventions and protective therapies to combat the virus and prevent its spread. Surface glycoproteins catalyzing the fusion of viral particles and host cells have proven to be an excellent target for antivirals as well as vaccines. This review focuses on recent advances for computational structure-based design of antivirals and vaccines targeting viral fusion machinery to control seasonal and emerging respiratory viruses.

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A protocol for adding knowledge to Wikidata: aligning resources on human coronaviruses

BMC Biology ◽

10.1186/s12915-020-00940-y ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Andra Waagmeester ◽

Egon L. Willighagen ◽

Andrew I. Su ◽

Martina Kutmon ◽

Jose Emilio Labra Gayo ◽

...

Keyword(s):

Common Ground ◽

Knowledge Bases ◽

Public Knowledge ◽

Medical Problems ◽

Human Coronavirus ◽

Data Schema ◽

Helping Others ◽

Human Coronaviruses ◽

The Right ◽

Human Coronavirus 229E

Abstract Background Pandemics, even more than other medical problems, require swift integration of knowledge. When caused by a new virus, understanding the underlying biology may help finding solutions. In a setting where there are a large number of loosely related projects and initiatives, we need common ground, also known as a “commons.” Wikidata, a public knowledge graph aligned with Wikipedia, is such a commons and uses unique identifiers to link knowledge in other knowledge bases. However, Wikidata may not always have the right schema for the urgent questions. In this paper, we address this problem by showing how a data schema required for the integration can be modeled with entity schemas represented by Shape Expressions. Results As a telling example, we describe the process of aligning resources on the genomes and proteomes of the SARS-CoV-2 virus and related viruses as well as how Shape Expressions can be defined for Wikidata to model the knowledge, helping others studying the SARS-CoV-2 pandemic. How this model can be used to make data between various resources interoperable is demonstrated by integrating data from NCBI (National Center for Biotechnology Information) Taxonomy, NCBI Genes, UniProt, and WikiPathways. Based on that model, a set of automated applications or bots were written for regular updates of these sources in Wikidata and added to a platform for automatically running these updates. Conclusions Although this workflow is developed and applied in the context of the COVID-19 pandemic, to demonstrate its broader applicability it was also applied to other human coronaviruses (MERS, SARS, human coronavirus NL63, human coronavirus 229E, human coronavirus HKU1, human coronavirus OC4).

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