Pterostilbene-mediated Nrf2 activation: Mechanistic insights on Keap1:Nrf2 interface.
The discovery of Keap1-Nrf2 protein-protein interaction (PPI) inhibitors has become a promising strategy to develop novel lead molecules against variety of stress. Hence, Keap1-Nrf2 system plays an important role in oxidative/electrophilic stress associated disorders. Our earlier studies identified pterostilbene (PTS), a natural analogue of resveratrol, as a potent Nrf2 activator and Keap1-Nrf2 PPI inhibitor as assessed by luciferase complementation assay. In this study, we further identified the potential of PTS in Nrf2 activation and ARE-driven downstream target genes expression by nuclear translocation experiments and ARE-luciferase reporter assay, respectively. Further, the luciferase complementation assay identified that PTS inhibits Keap1-Nrf2 PPI in both dose and time-dependent manner. Computational studies using molecular docking and dynamic simulation revealed that PTS directly interacts with the basic amino acids of kelch domain of Keap1 and perturb Keap1-Nrf2 interaction pattern. This manuscript not only shows the binding determinants of Keap1-Nrf2 proteins but also provides mechanistic insights on Nrf2 activation potential of PTS.
Department of Biotechnology, School of Bioengineering, SRM University, Kattankulathur 603203, Tamil Nadu, India.
Elango
E
Bhakkiyalakshmi
Department of Bioinformatics, School of Bioengineering, SRM University, Kattankulathur 603203, Tamil Nadu, India.
Kesavan
K
Dineshkumar
Department of Biotechnology, School of Bioengineering, SRM University, Kattankulathur 603203, Tamil Nadu, India.
Suresh
S
Karthik
SRM Research Institute, SRM University, Kattankulathur 603203, Tamil Nadu, India.
Dornadula
D
Sireesh
Department of Bioinformatics, School of Bioengineering, SRM University, Kattankulathur 603203, Tamil Nadu, India.
Waheeta
W
Hopper
Department of Radiology, Stanford University Medical Center, Stanford, CA 94304, USA.
Ramasamy
R
Paulmurugan
SRM Research Institute, SRM University, Kattankulathur 603203, Tamil Nadu, India. Electronic address: ramkumar.km@res.srmuniv.ac.in.
Kunka Mohanram
KM
Ramkumar
D006801:Humans; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000378:metabolism*; D062105:Molecular Docking Simulation; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D011485:Protein Binding; D013267:Stilbenes / Q000494:pharmacology*
C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D013267:Stilbenes; C107773:pterostilbene
ARE; Keap1; Molecular docking; Molecular dynamic simulation; Nrf2; Pterostilbene