title: Computational modeling on the recognition of the HRE motif by HIF-1: molecular docking and molecular dynamics studies.
abstract: Hypoxia inducible factor-1 (HIF-1) is a bHLH-family transcription factor that controls genes involved in glycolysis, angiogenesis, migration, as well as invasion factors that are important for tumor progression and metastasis. HIF-1, a heterodimer of HIF-1α and HIF-1β, binds to the hypoxia responsive element (HRE) present in the promoter regions of hypoxia responsive genes, such as vascular endothelial growth factor (VEGF). Neither the structure of free HIF-1 nor that of its complex with HRE is available. Computational modeling of the transcription factor-DNA complex has always been challenging due to their inherent flexibility and large conformational space. The present study aims to model the interaction between the DNA-binding domain of HIF-1 and HRE. Experiments showed that rigid macromolecular docking programs (HEX and GRAMM-X) failed to predict the optimal dimerization of individually modeled HIF-1 subunits. Hence, the HIF-1 heterodimer was modeled based on the phosphate system positive regulatory protein (PHO4) homodimer. The duplex VEGF-DNA segment containing HRE with flanking nucleotides was modeled in the B form and equilibrated via molecular dynamics (MD) simulation. A rigid docking approach was used to predict the crude binding mode of HIF-1 dimer with HRE, in which the putative contacts were found to be present. An MD simulation (5 ns) of the HIF-1-HRE complex in explicit water was performed to account for its flexibility and to optimize its interactions. All of the conserved amino acid residues were found to play roles in the recognition of HRE. The present work, which sheds light on the recognition of HRE by HIF-1, could be beneficial in the design of peptide or small molecule therapeutics that can mimic HIF-1 and bind with the HRE sequence.
authors.affiliation: School of Chemistry, Madurai Kamaraj University, Madurai, Tamil Nadu, India.
authors.forename: Pandian
authors.initials: P
authors.lastname: Sokkar
authors.forename: Vani
authors.initials: V
authors.lastname: Sathis
authors.forename: Murugesan
authors.initials: M
authors.lastname: Ramachandran
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics; D019281:Dimerization; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000737:chemistry* / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020218:Response Elements / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry* / Q000235:genetics; D040681:Structural Homology, Protein; D042461:Vascular Endothelial Growth Factor A / Q000737:chemistry* / Q000235:genetics; D014867:Water / Q000737:chemistry
chemical_list: C497396:ARNT protein, human; D000596:Amino Acids; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C060292:PHO4 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D014867:Water; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator