title: Molecular dynamics studies on the DNA-binding process of ERG.
abstract: The ETS family of transcription factors regulate gene targets by binding to a core GGAA DNA-sequence. The ETS factor ERG is required for homeostasis and lineage-specific functions in endothelial cells, some subset of haemopoietic cells and chondrocytes; its ectopic expression is linked to oncogenesis in multiple tissues. To date details of the DNA-binding process of ERG including DNA-sequence recognition outside the core GGAA-sequence are largely unknown. We combined available structural and experimental data to perform molecular dynamics simulations to study the DNA-binding process of ERG. In particular we were able to reproduce the ERG DNA-complex with a DNA-binding simulation starting in an unbound configuration with a final root-mean-square-deviation (RMSD) of 2.1 Å to the core ETS domain DNA-complex crystal structure. This allowed us to elucidate the relevance of amino acids involved in the formation of the ERG DNA-complex and to identify Arg385 as a novel key residue in the DNA-binding process. Moreover we were able to show that water-mediated hydrogen bonds are present between ERG and DNA in our simulations and that those interactions have the potential to achieve sequence recognition outside the GGAA core DNA-sequence. The methodology employed in this study shows the promising capabilities of modern molecular dynamics simulations in the field of protein DNA-interactions.
authors.affiliation: Department of Chemistry and Institute of Chemical Biology, Imperial College London, South Kensington SW7 2AZ, UK. i.gould@imperial.ac.uk.
authors.forename: Matthias G
authors.initials: MG
authors.lastname: Beuerle
authors.affiliation: National Heart and Lung Institute (NHLI) Vascular Sciences, Hammersmith Hospital, Imperial College London, London W12 0NN, UK.
authors.forename: Neil P
authors.initials: NP
authors.lastname: Dufton
authors.affiliation: National Heart and Lung Institute (NHLI) Vascular Sciences, Hammersmith Hospital, Imperial College London, London W12 0NN, UK.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Randi
authors.affiliation: Department of Chemistry and Institute of Chemical Biology, Imperial College London, South Kensington SW7 2AZ, UK. i.gould@imperial.ac.uk.
authors.forename: Ian R
authors.initials: IR
authors.lastname: Gould
mesh_terms: D001483:Base Sequence; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D006860:Hydrogen Bonding; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009154:Mutation; D054730:Protein Interaction Domains and Motifs; D000071230:Transcriptional Regulator ERG / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D000071230:Transcriptional Regulator ERG; D004247:DNA