In silico mechanistic analysis of IRF3 inactivation and high-risk HPV E6 species-dependent drug response.
The high-risk human papillomavirus E6 (hrHPV E6) protein has been widely studied due to its implication in cervical cancer. In response to viral threat, activated kinases phosphorylate the IRF3 autoinhibitory domain, inducing type1 interferon production. HPV circumvents the antiviral response through the possible E6 interaction with IRF3 and abrogates p53's apoptotic activity by recruiting E6-associated protein. However, the molecular mechanism of IRF3 inactivation by hrHPV E6 has not yet been delineated. Therefore, we explored this mechanism through in silico examination of protein-protein and protein-ligand docking, binding energy differences, and computational alanine mutagenesis. Our results suggested that the LxxLL motifs of IRF3 binds within the hydrophobic pocket of E6, precluding Ser-patch phosphorylation, necessary for IRF3 activation and interferon induction. This model was further supported by molecular dynamics simulation. Furthermore, protein-ligand docking and drug resistance modeling revealed that the polar patches in the pocket of E6, which are crucial for complex stability and ligand binding, are inconsistent among hrHPV species. Such variabilities pose a risk of treatment failure owing to point mutations that might render drugs ineffective, and allude to multi-drug therapy. Overall, this study reveals a novel perspective of innate immune suppression in HPV infections and suggests a plausible therapeutic intervention.
Department of Molecular Science and Technology, Ajou University, Suwon, 443-749, Korea.
Masaud
M
Shah
Department of Molecular Science and Technology, Ajou University, Suwon, 443-749, Korea.
Muhammad Ayaz
MA
Anwar
Department of Molecular Science and Technology, Ajou University, Suwon, 443-749, Korea.
Seolhee
S
Park
The Center of Excellence in Molecular Biology, University of the Punjab, Lahore, 54890, Pakistan.
Syyada Samra
SS
Jafri
Department of Molecular Science and Technology, Ajou University, Suwon, 443-749, Korea.
Sangdun
S
Choi
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology*; D003198:Computer Simulation; D024882:Drug Resistance, Viral / Q000187:drug effects; D005260:Female; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D007930:Leucine / Q000378:metabolism; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D025341:Principal Component Analysis; D011485:Protein Binding / Q000187:drug effects; D012307:Risk Factors; D013816:Thermodynamics
D000998:Antiviral Agents; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D008024:Ligands; D009856:Oncogene Proteins, Viral; D007930:Leucine