title: The Role of Dynamics and Allostery in the Inhibition of the eIF4E/eIF4G Translation Initiation Factor Complex.
abstract: Lack of regulation of the interaction between the eIF4E/eIF4G subunits of the translation initiation factor complex eIF4F is a hallmark of cancer. The inhibitor 4EGI-1 binds to eIF4E, thereby preventing association with eIF4G through an allosteric mechanism. NMR spectroscopy and MD simulations were used to obtain a mechanistic description of the role of correlated dynamics in this allosteric regulation. We show that binding of 4EGI-1 perturbs native correlated motions and increases correlated fluctuations in part of the eIF4G binding site.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, USA. nicola.salvi@ibs.fr.|Univ. Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale, Grenoble, France. nicola.salvi@ibs.fr.
authors.forename: Nicola
authors.identifier: 0000-0003-1515-6908
authors.initials: N
authors.lastname: Salvi
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, USA.
authors.forename: Evangelos
authors.initials: E
authors.lastname: Papadopoulos
authors.affiliation: Univ. Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale, Grenoble, France.
authors.forename: Martin
authors.initials: M
authors.lastname: Blackledge
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, USA. gerhard_wagner@hms.harvard.edu.
authors.forename: Gerhard
authors.identifier: 0000-0002-2063-4401
authors.initials: G
authors.lastname: Wagner
mesh_terms: D000494:Allosteric Regulation; D001665:Binding Sites; D039561:Eukaryotic Initiation Factor-4E / Q000737:chemistry / Q000378:metabolism*; D039603:Eukaryotic Initiation Factor-4G / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D060066:Protein Interaction Maps
chemical_list: D039561:Eukaryotic Initiation Factor-4E; D039603:Eukaryotic Initiation Factor-4G
keywords: NMR spectroscopy; allosterism; inhibitors; molecular dynamics; protein-protein interactions