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Proteins ; 89(2): 163-173, 2021 02.
Article in English | MEDLINE | ID: covidwho-745464


Human interleukin-6 (hIL-6) is a multifunctional cytokine that regulates immune and inflammatory responses in addition to metabolic and regenerative processes and cancer. hIL-6 binding to the IL-6 receptor (IL-6Rα) induces homodimerization and recruitment of the glycoprotein (gp130) to form a hexameric signaling complex. Anti-IL-6 and IL-6R antibodies are clinically approved inhibitors of IL-6 signaling pathway for treating rheumatoid arthritis and Castleman's disease, respectively. There is a potential to develop novel small molecule IL-6 antagonists derived from understanding the structural basis for IL-6/IL-6Rα interactions. Here, we combine homology modeling with extensive molecular dynamics (MD) simulations to examine the association of hIL-6 with IL-6Rα. A comparison with MD of apo hIL-6 reveals that the binding of hIL-6 to IL-6Rα induces structural and dynamic rearrangements in the AB loop region of hIL-6, disrupting intraprotein contacts and increasing the flexibility of residues 48 to 58 of the AB loop. In contrast, due to the involvement of residues 59 to 78 in forming contacts with the receptor, these residues of the AB loop are observed to rigidify in the presence of the receptor. The binary complex is primarily stabilized by two pairs of salt bridges, Arg181 (hIL-6)- Glu182 (IL-6Rα) and Arg184 (hIL-6)- Glu183 (IL-6Rα) as well as hydrophobic and aromatic stacking interactions mediated essentially by Phe residues in both proteins. An interplay of electrostatic, hydrophobic, hydrogen bonding, and aromatic stacking interactions facilitates the formation of the hIL-6/IL-6Rα complex.

Apoproteins/chemistry , Interleukin-6/chemistry , Molecular Dynamics Simulation , Receptors, Interleukin-6/chemistry , Apoproteins/metabolism , Binding Sites , Crystallography, X-Ray , Humans , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Interleukin-6/metabolism , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Receptors, Interleukin-6/metabolism , Static Electricity , Structural Homology, Protein , Thermodynamics
J Mol Graph Model ; 103: 107803, 2021 03.
Article in English | MEDLINE | ID: covidwho-957225


In this study, the binding strength of 32 diastereomers of nelfinavir, a proposed drug for the treatment of COVID-19, was considered against main protease. Molecular docking was used to determine the most potent diastereomers. The top three diastereomers along with apo form of protein were then considered via molecular dynamics simulation and MM-GBSA method. During the simulation, the structural consideration of four proteins considered was carried out using RMSD, RMSF, Rg and hydrogen bond analysis tools. Our data demonstrated that the effect of nelfinavir RSRSR stereoisomer on protein stability and compactness is higher than the other. We also found from the hydrogen bond analysis that this important diastereomer form three hydrogen bonds with the residues of Glu166, Gly143 and Hie41. MM/GBSA analysis showed that the binding strength of RSRSR is more than other stereoisomers and that the main contributions to binding energy are vdW and electronic terms. The nelfinavir RSRSR stereoisomer introduced in this study may be effective in the treatment of COVID-19.

Antiviral Agents/chemistry , Apoproteins/antagonists & inhibitors , Coronavirus 3C Proteases/antagonists & inhibitors , Nelfinavir/chemistry , Protease Inhibitors/chemistry , SARS-CoV-2/chemistry , Antiviral Agents/metabolism , Apoproteins/chemistry , Apoproteins/metabolism , Binding Sites , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Hydrogen Bonding , Kinetics , Molecular Docking Simulation , Molecular Dynamics Simulation , Nelfinavir/metabolism , Protease Inhibitors/metabolism , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , SARS-CoV-2/enzymology , Stereoisomerism , Thermodynamics
Biomol NMR Assign ; 14(2): 339-346, 2020 10.
Article in English | MEDLINE | ID: covidwho-716391


The SARS-CoV-2 genome encodes for approximately 30 proteins. Within the international project COVID19-NMR, we distribute the spectroscopic analysis of the viral proteins and RNA. Here, we report NMR chemical shift assignments for the protein Nsp3b, a domain of Nsp3. The 217-kDa large Nsp3 protein contains multiple structurally independent, yet functionally related domains including the viral papain-like protease and Nsp3b, a macrodomain (MD). In general, the MDs of SARS-CoV and MERS-CoV were suggested to play a key role in viral replication by modulating the immune response of the host. The MDs are structurally conserved. They most likely remove ADP-ribose, a common posttranslational modification, from protein side chains. This de-ADP ribosylating function has potentially evolved to protect the virus from the anti-viral ADP-ribosylation catalyzed by poly-ADP-ribose polymerases (PARPs), which in turn are triggered by pathogen-associated sensing of the host immune system. This renders the SARS-CoV-2 Nsp3b a highly relevant drug target in the viral replication process. We here report the near-complete NMR backbone resonance assignment (1H, 13C, 15N) of the putative Nsp3b MD in its apo form and in complex with ADP-ribose. Furthermore, we derive the secondary structure of Nsp3b in solution. In addition, 15N-relaxation data suggest an ordered, rigid core of the MD structure. These data will provide a basis for NMR investigations targeted at obtaining small-molecule inhibitors interfering with the catalytic activity of Nsp3b.

Adenosine Diphosphate Ribose/metabolism , Apoproteins/chemistry , Betacoronavirus/metabolism , Carbon-13 Magnetic Resonance Spectroscopy , Nitrogen Isotopes/chemistry , Proton Magnetic Resonance Spectroscopy , Viral Nonstructural Proteins/chemistry , Amino Acid Sequence , Apoproteins/metabolism , Protein Domains , Protein Structure, Secondary , SARS-CoV-2 , Viral Nonstructural Proteins/metabolism