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1.
RNA ; 28(2): 227-238, 2022 02.
Article in English | MEDLINE | ID: covidwho-1533393

ABSTRACT

The Bacillus subtilis genome is predicted to encode numerous ribonucleases, including four 3' exoribonucleases that have been characterized to some extent. A strain containing gene knockouts of all four known 3' exoribonucleases is viable, suggesting that one or more additional RNases remain to be discovered. A protein extract from the quadruple RNase mutant strain was fractionated and RNase activity was followed, resulting in the identification of an enzyme activity catalyzed by the YloC protein. YloC is an endoribonuclease and is a member of the highly conserved "YicC family" of proteins that is widespread in bacteria. YloC is a metal-dependent enzyme that catalyzes the cleavage of single-stranded RNA, preferentially at U residues, and exists in an oligomeric form, most likely a hexamer. As such, YloC shares some characteristics with the SARS-CoV Nsp15 endoribonuclease. While the in vivo function of YloC in B. subtilis is yet to be determined, YloC was found to act similarly to YicC in an Escherichia coli in vivo assay that assesses decay of the small RNA, RyhB. Thus, YloC may play a role in small RNA regulation.


Subject(s)
Bacillus subtilis/genetics , Endoribonucleases/genetics , Endoribonucleases/metabolism , Bacillus subtilis/enzymology , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Endoribonucleases/chemistry , Escherichia coli/genetics , Escherichia coli/metabolism , Escherichia coli Proteins/metabolism , Gene Expression Regulation, Bacterial , Microorganisms, Genetically-Modified , Mutation , RNA Stability , RNA, Bacterial/chemistry , RNA, Bacterial/metabolism , Ribonucleases/genetics , Ribonucleases/metabolism , Substrate Specificity , Viral Nonstructural Proteins/metabolism
2.
J Biol Chem ; 297(4): 101218, 2021 10.
Article in English | MEDLINE | ID: covidwho-1433454

ABSTRACT

The SARS-CoV-2 replication-transcription complex is an assembly of nonstructural viral proteins that collectively act to reproduce the viral genome and generate mRNA transcripts. While the structures of the individual proteins involved are known, how they assemble into a functioning superstructure is not. Applying molecular modeling tools, including protein-protein docking, to the available structures of nsp7-nsp16 and the nucleocapsid, we have constructed an atomistic model of how these proteins associate. Our principal finding is that the complex is hexameric, centered on nsp15. The nsp15 hexamer is capped on two faces by trimers of nsp14/nsp16/(nsp10)2, which then recruit six nsp12/nsp7/(nsp8)2 polymerase subunits to the complex. To this, six subunits of nsp13 are arranged around the superstructure, but not evenly distributed. Polymerase subunits that coordinate dimers of nsp13 are capable of binding the nucleocapsid, which positions the 5'-UTR TRS-L RNA over the polymerase active site, a state distinguishing transcription from replication. Analysis of the viral RNA path through the complex indicates the dsRNA that exits the polymerase passes over the nsp14 exonuclease and nsp15 endonuclease sites before being unwound by a convergence of zinc fingers from nsp10 and nsp14. The template strand is then directed away from the complex, while the nascent strand is directed to the sites responsible for mRNA capping. The model presents a cohesive picture of the multiple functions of the coronavirus replication-transcription complex and addresses fundamental questions related to proofreading, template switching, mRNA capping, and the role of the endonuclease.


Subject(s)
Endoribonucleases/metabolism , Models, Molecular , SARS-CoV-2/metabolism , Viral Nonstructural Proteins/metabolism , Binding Sites , COVID-19/pathology , COVID-19/virology , Dimerization , Endoribonucleases/chemistry , Endoribonucleases/genetics , Humans , Molecular Docking Simulation , Protein Structure, Quaternary , RNA, Double-Stranded/chemistry , RNA, Double-Stranded/metabolism , SARS-CoV-2/isolation & purification , Transcription, Genetic , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/genetics , Virus Replication
3.
Nat Commun ; 12(1): 636, 2021 01 27.
Article in English | MEDLINE | ID: covidwho-1387325

ABSTRACT

Nsp15, a uridine specific endoribonuclease conserved across coronaviruses, processes viral RNA to evade detection by host defense systems. Crystal structures of Nsp15 from different coronaviruses have shown a common hexameric assembly, yet how the enzyme recognizes and processes RNA remains poorly understood. Here we report a series of cryo-EM reconstructions of SARS-CoV-2 Nsp15, in both apo and UTP-bound states. The cryo-EM reconstructions, combined with biochemistry, mass spectrometry, and molecular dynamics, expose molecular details of how critical active site residues recognize uridine and facilitate catalysis of the phosphodiester bond. Mass spectrometry revealed the accumulation of cyclic phosphate cleavage products, while analysis of the apo and UTP-bound datasets revealed conformational dynamics not observed by crystal structures that are likely important to facilitate substrate recognition and regulate nuclease activity. Collectively, these findings advance understanding of how Nsp15 processes viral RNA and provide a structural framework for the development of new therapeutics.


Subject(s)
Endoribonucleases/chemistry , Endoribonucleases/ultrastructure , SARS-CoV-2/enzymology , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/ultrastructure , Amino Acid Sequence , Catalytic Domain , Cryoelectron Microscopy , Endoribonucleases/metabolism , Models, Chemical , Models, Molecular , SARS-CoV-2/chemistry , Uridine Triphosphate/metabolism , Viral Nonstructural Proteins/metabolism
4.
J Mol Model ; 27(6): 160, 2021 May 08.
Article in English | MEDLINE | ID: covidwho-1219702

ABSTRACT

Coronavirus infectious disease 2019 (COVID-19), a viral infection caused by a novel coronavirus (nCoV), continues to emerge as a serious threat to public health. This pandemic caused by SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2) has infected globally with 1,550,000 plus deaths to date, representing a high risk to public health. No effective drug or vaccine is available to curb down this deadly virus. The expedition for searching for a potential drug or vaccine against COVID-19 is of massive potential and favour to the community. This study is focused on finding an effective natural compound that can be processed further into a potential inhibitor to check the activity of SARS-CoV-2 with minimal side effects targeting NSP15 protein, which belongs to the EndoU enzyme family. The natural screening suggested two efficient compounds (PubChem ID: 95372568 and 1776037) with dihydroxyphenyl region of the compound, found to be important in the interaction with the viral protein showing promising activity which may act as a potent lead inhibitory molecule against the virus. In combination with virtual screening, modelling, drug likeliness, molecular docking, and 500 ns cumulative molecular dynamics simulations (100 ns for each complex) along with the decomposition analysis to calculate and confirm the stability and fold, we propose 95372568 and 1776037 as novel compounds of natural origin capable of getting developed into potent lead molecules against SARS-CoV-2 target protein NSP15.


Subject(s)
Antiviral Agents/chemistry , Biological Products/chemistry , COVID-19 , Computational Biology , Endoribonucleases , Molecular Docking Simulation , Molecular Dynamics Simulation , SARS-CoV-2/chemistry , Viral Nonstructural Proteins , Antiviral Agents/therapeutic use , Biological Products/therapeutic use , COVID-19/drug therapy , Endoribonucleases/chemistry , Humans , Viral Nonstructural Proteins/chemistry
5.
Front Immunol ; 11: 1554, 2020.
Article in English | MEDLINE | ID: covidwho-1194588

ABSTRACT

The RNase T2 family consists of evolutionarily conserved endonucleases that express in many different species, including animals, plants, protozoans, bacteria, and viruses. The main biological roles of these ribonucleases are cleaving or degrading RNA substrates. They preferentially cleave single-stranded RNA molecules between purine and uridine residues to generate two nucleotide fragments with 2'3'-cyclic phosphate adenosine/guanosine terminus and uridine residue, respectively. Accumulating studies have revealed that RNase T2 is critical for the pathophysiology of inflammation and cancer. In this review, we introduce the distribution, structure, and functions of RNase T2, its differential roles in inflammation and cancer, and the perspective for its research and related applications in medicine.


Subject(s)
Disease Susceptibility , Endoribonucleases/genetics , Endoribonucleases/metabolism , Inflammation/etiology , Inflammation/metabolism , Neoplasms/etiology , Neoplasms/metabolism , Animals , Biomarkers , Cellular Microenvironment/immunology , Disease Susceptibility/immunology , Endoribonucleases/chemistry , Humans , Immune System/immunology , Immune System/metabolism , Immunomodulation , Inflammation/pathology , Neoplasms/pathology , Structure-Activity Relationship
6.
Food Chem ; 346: 128933, 2021 Jun 01.
Article in English | MEDLINE | ID: covidwho-1082161

ABSTRACT

Immensely aggravated situation of COVID-19 has pushed the scientific community towards developing novel therapeutics to fight the pandemic. Small molecules can possibly prevent the spreading infection by targeting specific vital components of the viral genome. Non-structural protein 15 (Nsp15) has emerged as a promising target for such inhibitor molecules. In this investigation, we docked bioactive molecules of tea onto the active site of Nsp15. Based on their docking scores, top three molecules (Barrigenol, Kaempferol, and Myricetin) were selected and their conformational behavior was analyzed via molecular dynamics simulations and MMPBSA calculations. The results indicated that the protein had well adapted the ligands in the binding pocket thereby forming stable complexes. These molecules displayed low binding energy during MMPBSA calculations, substantiating their strong association with Nsp15. The inhibitory potential of these molecules could further be examined by in-vivo and in-vitro investigations to validate their use as inhibitors against Nsp15 of SARS-CoV2.


Subject(s)
Antiviral Agents/pharmacology , Computer Simulation , Endoribonucleases/antagonists & inhibitors , Plant Extracts/pharmacology , Tea/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Catalytic Domain , Endoribonucleases/chemistry , Endoribonucleases/metabolism , Humans , Ligands , Molecular Dynamics Simulation , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolism
7.
Commun Biol ; 4(1): 193, 2021 02 09.
Article in English | MEDLINE | ID: covidwho-1075259

ABSTRACT

SARS-CoV-2 Nsp15 is a uridine-specific endoribonuclease with C-terminal catalytic domain belonging to the EndoU family that is highly conserved in coronaviruses. As endoribonuclease activity seems to be responsible for the interference with the innate immune response, Nsp15 emerges as an attractive target for therapeutic intervention. Here we report the first structures with bound nucleotides and show how the enzyme specifically recognizes uridine moiety. In addition to a uridine site we present evidence for a second base binding site that can accommodate any base. The structure with a transition state analog, uridine vanadate, confirms interactions key to catalytic mechanisms. In the presence of manganese ions, the enzyme cleaves unpaired RNAs. This acquired knowledge was instrumental in identifying Tipiracil, an FDA approved drug that is used in the treatment of colorectal cancer, as a potential anti-COVID-19 drug. Using crystallography, biochemical, and whole-cell assays, we demonstrate that Tipiracil inhibits SARS-CoV-2 Nsp15 by interacting with the uridine binding pocket in the enzyme's active site. Our findings provide new insights for the development of uracil scaffold-based drugs.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/virology , Endoribonucleases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Pyrrolidines/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology , Thymine/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , A549 Cells , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Catalytic Domain , Crystallography, X-Ray , Endoribonucleases/chemistry , Endoribonucleases/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Humans , Ligands , Models, Molecular , Protein Conformation , Pyrrolidines/chemistry , Pyrrolidines/pharmacokinetics , Thymine/chemistry , Thymine/pharmacokinetics , Uridine/metabolism , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolism
8.
J Chem Inf Model ; 60(12): 5853-5865, 2020 12 28.
Article in English | MEDLINE | ID: covidwho-1065772

ABSTRACT

Tremendous effort has been given to the development of diagnostic tests, preventive vaccines, and therapeutic medicines for coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Much of this development has been based on the reference genome collected on January 5, 2020. Based on the genotyping of 15 140 genome samples collected up to June 1, 2020, we report that SARS-CoV-2 has undergone 8309 single mutations which can be clustered into six subtypes. We introduce mutation ratio and mutation h-index to characterize the protein conservativeness and unveil that SARS-CoV-2 envelope protein, main protease, and endoribonuclease protein are relatively conservative, while SARS-CoV-2 nucleocapsid protein, spike protein, and papain-like protease are relatively nonconservative. In particular, we have identified mutations on 40% of nucleotides in the nucleocapsid gene in the population level, signaling potential impacts on the ongoing development of COVID-19 diagnosis, vaccines, and antibody and small-molecular drugs.


Subject(s)
COVID-19 , SARS-CoV-2/classification , SARS-CoV-2/metabolism , Antibodies, Viral/metabolism , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19/therapy , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/genetics , Coronavirus Envelope Proteins/chemistry , Coronavirus Envelope Proteins/genetics , Coronavirus Nucleocapsid Proteins/chemistry , Coronavirus Nucleocapsid Proteins/genetics , Coronavirus Papain-Like Proteases/chemistry , Coronavirus Papain-Like Proteases/genetics , Endoribonucleases/chemistry , Endoribonucleases/genetics , Genome, Viral , Genotype , Geography , Humans , Mutant Proteins/chemistry , Mutant Proteins/genetics , Mutation , Phosphoproteins/chemistry , Phosphoproteins/genetics , Protein Conformation , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Vaccines/metabolism , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/genetics
9.
Arch Biochem Biophys ; 700: 108771, 2021 03 30.
Article in English | MEDLINE | ID: covidwho-1039239

ABSTRACT

In the current study, a structure-based virtual screening paradigm was used to screen a small molecular database against the Non-structural protein 15 (Nsp15) endoribonuclease of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The SARS-CoV-2 is the causative agent of the recent outbreak of coronavirus disease 2019 (COVID-19) which left the entire world locked down inside the home. A multi-step molecular docking study was performed against antiviral specific compounds (~8722) collected from the Asinex antiviral database. The less or non-interacting molecules were wiped out sequentially in the molecular docking. Further, MM-GBSA based binding free energy was estimated for 26 compounds which shows a high affinity towards the Nsp15. The drug-likeness and pharmacokinetic parameters of all 26 compounds were explored, and five molecules were found to have an acceptable pharmacokinetic profile. Overall, the Glide-XP docking score and Prime-MM-GBSA binding free energy of the selected molecules were explained strong interaction potentiality towards the Nsp15 endoribonuclease. The dynamic behavior of each molecule with Nsp15 was assessed using conventional molecular dynamics (MD) simulation. The MD simulation information was strongly favors the Nsp15 and each identified ligand stability in dynamic condition. Finally, from the MD simulation trajectories, the binding free energy was estimated using the MM-PBSA method. Hence, the proposed final five molecules might be considered as potential Nsp15 modulators for SARS-CoV-2 inhibition.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/virology , Endoribonucleases/antagonists & inhibitors , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , COVID-19/metabolism , Databases, Chemical , Drug Evaluation, Preclinical , Endoribonucleases/chemistry , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Humans , In Vitro Techniques , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Molecular Structure , User-Computer Interface , Viral Nonstructural Proteins/chemistry
10.
Eur J Pharmacol ; 892: 173779, 2021 Feb 05.
Article in English | MEDLINE | ID: covidwho-959761

ABSTRACT

The rapid outbreak of the COVID-19 also known as SARS-CoV2 has been declared pandemic with serious global concern. As there is no effective therapeutic against COVID-19, there is an urgent need for explicit treatment against it. The focused objective of the current study is to propose promising drug candidates against the newly identified potential therapeutic target (endonuclease, NSP15) of SARS-CoV2. NSP15 is an attractive druggable target due to its critical role in SARS-CoV2 replication and virulence in addition to interference with the host immune system. Here in the present study, we integrated the high throughput computational screening and dynamic simulation approach to identify the most promising candidate lead compound against NSP15.5-fluoro-2-oxo-1H-pyrazine-3-carboxamide (favipiravir), (3R,4R, 5R)-3,4-Bis(benzyloxy)-5-((benzyloxy) methyl) dihydrofuran-2(3H)-one) remedesivir, 1,3-thiazol-5-ylmethyl N-[(2S,3S, 5S)-3-hydroxy-5-[[(2 S)-3-methyl-2-[[methyl-[(2-propan-2-yl-1,3-thiazol-4-yl)methyl]carbamoyl]amino]butanoyl]amino]-1,6-diphenylhexan-2-yl]carbamate (ritonavir), ethyl (3R,4R, 5S)-4-acetamido-5-amino-3-pentan-3-yloxycyclohexene-1-carboxylate (oseltamivir), and (2 S)-N-[(2S,4S, 5S)-5-[[2-(2,6-dimethylphenoxy)acetyl]amino]-4-hydroxy-1,6-diphenylhexan-2-yl]-3-methyl-2-(2-oxo-1,3-diazinan-1-yl)butanamide (lopinavir) were chosen as a training set to generate the pharmacophore model. A dataset of ~140,000 compounds library was screened against the designed pharmacophore model and 10 unique compounds were selected that passed successfully through geometry constraints, Lipinski Rule of 5, and ADME/Tox filters along with a strong binding affinity for NSP15 binding cavity. The best fit compound was selected for dynamic simulation to have detailed structural features critical for binding with the NSP15 protein. Given our detailed integrative computational analysis, a Small molecule (3,3-Dimethyl-N-[4-(1-piperidinylcarbonyl) phenyl] butanamide) with drug-like properties and high binding affinity with the NSP15 is proposed as a most promising potential drug against COVID-19. The current computational integrative approach may complement high-throughput screening and the shortlisted small molecule may contribute to selective targeting of NSP15 to stop the replication of SARS-CoV2.


Subject(s)
Antiviral Agents/pharmacology , Benzamides/pharmacology , COVID-19/metabolism , Endoribonucleases/metabolism , Piperidines/pharmacology , SARS-CoV-2 , Viral Nonstructural Proteins/metabolism , Antiviral Agents/pharmacokinetics , Antiviral Agents/toxicity , Benzamides/pharmacokinetics , Drug Design , Endoribonucleases/chemistry , High-Throughput Screening Assays , Molecular Docking Simulation , Molecular Dynamics Simulation , Piperidines/pharmacokinetics , Viral Nonstructural Proteins/chemistry
11.
Molecules ; 25(23)2020 Dec 01.
Article in English | MEDLINE | ID: covidwho-953409

ABSTRACT

SARS-CoV-2 is a positive-stranded RNA virus that bundles its genomic material as messenger-sense RNA in infectious virions and replicates these genomes through RNA intermediates. Several virus-encoded nonstructural proteins play a key role during the viral life cycle. Endoribonuclease NSP15 is vital for the replication and life cycle of the virus, and is thus considered a compelling druggable target. Here, we performed a combination of multiscoring virtual screening and molecular docking of a library of 1624 natural compounds (Nuclei of Bioassays, Ecophysiology and Biosynthesis of Natural Products (NuBBE) database) on the active sites of NSP15 (PDB:6VWW). After sequential high-throughput screening by LibDock and GOLD, docking optimization by CDOCKER, and final scoring by calculating binding energies, top-ranked compounds NuBBE-1970 and NuBBE-242 were further investigated via an indepth molecular-docking and molecular-dynamics simulation of 60 ns, which revealed that the binding of these two compounds with active site residues of NSP15 was sufficiently strong and stable. The findings strongly suggest that further optimization and clinical investigations of these potent compounds may lead to effective SARS-CoV-2 treatment.


Subject(s)
Antiviral Agents/pharmacology , Endoribonucleases/chemistry , High-Throughput Screening Assays/methods , Viral Nonstructural Proteins/chemistry , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , COVID-19/drug therapy , Catalytic Domain , Endoribonucleases/metabolism , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Viral Nonstructural Proteins/metabolism
12.
RNA Biol ; 18(4): 447-456, 2021 04.
Article in English | MEDLINE | ID: covidwho-786941

ABSTRACT

The SARS-CoV-2, a positive-sense single-stranded RNA Coronavirus, is a global threat to human health. Thus, understanding its life cycle mechanistically would be important to facilitate the design of antiviral drugs. A key aspect of viral progression is the synthesis of viral proteins by the ribosome of the human host. In Coronaviruses, this process is regulated by the viral 5' and 3' untranslated regions (UTRs), but the precise regulatory mechanism has not yet been well understood. In particular, the 5'-UTR of the viral genome is most likely involved in translation initiation of viral proteins. Here, we performed inline probing and RNase V1 probing to establish a model of the secondary structure of SARS-CoV-2 5'-UTR. We found that the 5'-UTR contains stable structures including a very stable four-way junction close to the AUG start codon. Sequence alignment analysis of SARS-CoV-2 variants 5'-UTRs revealed a highly conserved structure with few co-variations that confirmed our secondary structure model based on probing experiments.


Subject(s)
5' Untranslated Regions , RNA, Viral/chemistry , SARS-CoV-2/genetics , Codon, Terminator , Endoribonucleases/chemistry , Endoribonucleases/metabolism , Nucleic Acid Conformation , RNA, Viral/metabolism , Viral Nonstructural Proteins/genetics
13.
J Allergy Clin Immunol ; 146(2): 330-331, 2020 08.
Article in English | MEDLINE | ID: covidwho-597639
14.
Protein Sci ; 29(7): 1596-1605, 2020 07.
Article in English | MEDLINE | ID: covidwho-71902

ABSTRACT

Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) is rapidly spreading around the world. There is no existing vaccine or proven drug to prevent infections and stop virus proliferation. Although this virus is similar to human and animal SARS-CoVs and Middle East Respiratory Syndrome coronavirus (MERS-CoVs), the detailed information about SARS-CoV-2 proteins structures and functions is urgently needed to rapidly develop effective vaccines, antibodies, and antivirals. We applied high-throughput protein production and structure determination pipeline at the Center for Structural Genomics of Infectious Diseases to produce SARS-CoV-2 proteins and structures. Here we report two high-resolution crystal structures of endoribonuclease Nsp15/NendoU. We compare these structures with previously reported homologs from SARS and MERS coronaviruses.


Subject(s)
Betacoronavirus/chemistry , Endoribonucleases/chemistry , Middle East Respiratory Syndrome Coronavirus/chemistry , Oligonucleotides/chemistry , SARS Virus/chemistry , Viral Nonstructural Proteins/chemistry , Amino Acid Sequence , Betacoronavirus/genetics , Betacoronavirus/metabolism , Catalytic Domain , Cloning, Molecular , Crystallography, X-Ray , Endoribonucleases/genetics , Endoribonucleases/metabolism , Escherichia coli/genetics , Escherichia coli/metabolism , Gene Expression , Genetic Vectors/chemistry , Genetic Vectors/metabolism , Humans , Middle East Respiratory Syndrome Coronavirus/genetics , Middle East Respiratory Syndrome Coronavirus/metabolism , Models, Molecular , Oligonucleotides/metabolism , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , SARS Virus/genetics , SARS Virus/metabolism , SARS-CoV-2 , Sequence Alignment , Sequence Homology, Amino Acid , Substrate Specificity , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolism
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