Structural analysis of H1N1 and H7N9 influenza A virus PA in the absence of PB1

Moen, Spencer O.; Abendroth, Jan; Fairman, J.W.; Baydo, Ruth; Bullen, Jameson; Kirkwood, Jennifer L.; Barnes, Steve; Raymond, Amy; Begley, Darren W.; Henkel, Greg; McCormack, Ken; Tam, Vincent C.; Phan, Isabelle; Staker, Bart L.; Stacy, Robin; Myler, Peter J.; Lorimer, Don; Edwards, Thomas E.

doi:10.1038/srep05944

Cited by 10 publications

(4 citation statements)

References 35 publications

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“…This PA C domain resembles a dragon's head that clamps the PB1 N peptide. As shown in Figure B, the base of this pocket overlaps between the crystal structures of the PB1 N ‐bound PA C domain (in dark blue), the full polymerase heterotrimer (in gray), and the apo PA C domain (in light blue). In contrast, there is less overlap at the periphery, meaning that the binding groove is slightly more narrow in the structure of the PB1 N ‐bound PA C compared to the two other crystal structures.…”

Section: Strategies To Interfere With the Influenza Virus Polymerasementioning

confidence: 94%

“…(A) Location in the FluA polymerase crystal structure (PDB: 4WSB) of the two PPI domains, which have been targeted by peptides or small molecules. (B) Closeup showing a superposition of the crystal structures of the PA C ‐PB1 N interface (PDB: 3CM8) on that of the FluA polymerase (light gray) and the apo form of PA C (light blue; PDB: 4IUJ). (C) Closeup showing a superposition of the crystal structure of the PB1 C ‐PB2 N interface (PDB: 3A1G) on the FluA polymerase complex, in light gray.…”

Section: Strategies To Interfere With the Influenza Virus Polymerasementioning

confidence: 99%

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The Influenza Virus Polymerase Complex: An Update on Its Structure, Functions, and Significance for Antiviral Drug Design

Stevaert

Naesens

2016

Medicinal Research Reviews

136

151

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Influenza viruses cause seasonal epidemics and pandemic outbreaks associated with significant morbidity and mortality, and a huge cost. Since resistance to the existing anti‐influenza drugs is rising, innovative inhibitors with a different mode of action are urgently needed. The influenza polymerase complex is widely recognized as a key drug target, given its critical role in virus replication and high degree of conservation among influenza A (of human or zoonotic origin) and B viruses. We here review the major progress that has been made in recent years in unravelling the structure and functions of this protein complex, enabling structure‐aided drug design toward the core regions of the PA endonuclease, PB1 polymerase, or cap‐binding PB2 subunit. Alternatively, inhibitors may target a protein–protein interaction site, a cellular factor involved in viral RNA synthesis, the viral RNA itself, or the nucleoprotein component of the viral ribonucleoprotein. The latest advances made for these diverse pharmacological targets have yielded agents in advanced (i.e., favipiravir and VX‐787) or early clinical testing, besides several experimental inhibitors in various stages of development, which are all covered here.

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Section: Strategies To Interfere With the Influenza Virus Polymerasementioning

confidence: 94%

Section: Strategies To Interfere With the Influenza Virus Polymerasementioning

confidence: 99%

The Influenza Virus Polymerase Complex: An Update on Its Structure, Functions, and Significance for Antiviral Drug Design

Stevaert

Naesens

2016

Medicinal Research Reviews

136

151

View full text Add to dashboard Cite

show abstract

“…In PB2, allysine K718 was also highly conserved ( Figure 3 D) across 986 sequences from 48 IAV subtypes ( Supplementary Table S2 ), but not within the PB2 of IAV, IBV or ICV ( Figure 3 E). In the PA structure, K102 and K104 were located in the loop region of its critical N-terminal endonuclease domain ( Figure 3 F), which also binds PB2 [ 44 ]. Furthermore, K102 is vital for PA endonuclease activity, particularly for its mRNA cap-binding activity [ 45 ] and consequently for IAV growth [ 46 ].…”

Section: Resultsmentioning

confidence: 99%

Acetylation, Methylation and Allysine Modification Profile of Viral and Host Proteins during Influenza A Virus Infection

Ahmed

Kleffmann

Husain

2021

Viruses

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Protein modifications dynamically occur and regulate biological processes in all organisms. Towards understanding the significance of protein modifications in influenza virus infection, we performed a global mass spectrometry screen followed by bioinformatics analyses of acetylation, methylation and allysine modification in human lung epithelial cells in response to influenza A virus infection. We discovered 8 out of 10 major viral proteins and 245 out of 2280 host proteins detected to be differentially modified by three modifications in infected cells. Some of the identified proteins were modified on multiple amino acids residues and by more than one modification; the latter occurred either on different or same residues. Most of the modified residues in viral proteins were conserved across >40 subtypes of influenza A virus, and influenza B or C viruses and located on the protein surface. Importantly, many of those residues have already been determined to be critical for the influenza A virus. Similarly, many modified residues in host proteins were conserved across influenza A virus hosts like humans, birds, and pigs. Finally, host proteins undergoing the three modifications clustered in common functional networks of metabolic, cytoskeletal, and RNA processes, all of which are known to be exploited by the influenza A virus.

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“…The hydrophobic pockets of PA C -PB1 N crystal structure were located on the molecular surface. Hydrophobic pockets would facilitate an array of hydrogen bonds in the PA C -PB1 N (Moen et al, 2014). Hydrophobic interactions could be a significant contribution to the binding energy (Obayashi et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Designing of Disulfide Cyclic Peptide for Inhibiting Polymerase A and B1 (PA<sub>C</sub>-PB1<sub>N</sub>) in H1N1 Virus using Molecular Simulation Approach

Tambunan¹,

Nasution²,

Parikesit³

et al. 2016

OnLine Journal of Biological Sciences

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Abstract:The drug resistance A/H1N1 flu virus is emerging rapidly. Therefore, looking for potential therapy is very important. PB2, PB and PA are subunits of viral RNA-dependent RNA polymerase (RdRp). They play an important role in viral replication. The PA and PB1 binding sites can be considered as potential targets for the development of new influenza drugs. The peptide inhibitors can be designed specifically due to their highpreferred activity. In this study, the cyclic peptide ligands were designed based on the crystal structure of PA C -PB1 N in the surface of the molecule, resulting 1728 cyclopentadienyl compounds. The MOE 2008.10 software was utilized for molecular docking and dynamics simulation approach, while Lipinski's Rules of Five were utilized to evaluate the feasibility of drug candidates. Thus, molecular dynamics simulation was applied, in order to facilitate the interaction between the ligand and enzyme. The simulations have successfully produced two cyclopentyl peptides, namely CKKTC and CKTTC, which results in both ligands providing a potent inhibitor of polymerase PA C -PB1 N of Influenza A/2009 (H1N1).

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Structural analysis of H1N1 and H7N9 influenza A virus PA in the absence of PB1

Cited by 10 publications

References 35 publications

The Influenza Virus Polymerase Complex: An Update on Its Structure, Functions, and Significance for Antiviral Drug Design

The Influenza Virus Polymerase Complex: An Update on Its Structure, Functions, and Significance for Antiviral Drug Design

Acetylation, Methylation and Allysine Modification Profile of Viral and Host Proteins during Influenza A Virus Infection

Designing of Disulfide Cyclic Peptide for Inhibiting Polymerase A and B1 (PA<sub>C</sub>-PB1<sub>N</sub>) in H1N1 Virus using Molecular Simulation Approach

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