title: Active-Site-Directed Inhibitors of Prolyl Oligopeptidase Abolish Its Conformational Dynamics.
abstract: Deciphering conformational dynamics is crucial for understanding the biological functions of proteins and for designing compounds targeting them. In particular, providing an accurate description of microsecond-millisecond motions opens the opportunity for regulating protein-protein interactions (PPIs) by modulating the dynamics of one interacting partner. Here we analyzed the conformational dynamics of prolyl oligopeptidase (POP) and the effects of active-site-directed inhibitors on the dynamics. We used an integrated structural biology approach based on NMR spectroscopy and SAXS experiments complemented by MD simulations. We found that POP is in a slow equilibrium in solution between open and closed conformations, and that inhibitors effectively abolished this equilibrium by stabilizing the enzyme in the closed conformation.
authors.affiliation: Chemistry and Molecular Pharmacology Program, Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028, Barcelona, Spain.|Department of Organic Chemistry, University of Barcelona, Martí i Franquès, 1-11, 08028, Barcelona, Spain.
authors.forename: Abraham
authors.initials: A
authors.lastname: López
authors.affiliation: Centre de Biochimie Structurale, INSERM U1054, CNRS UMR 5048, Université de Montpellier 1 and 2, 29 rue de Navacelles, 34090, Montpellier, France.
authors.forename: Fátima
authors.initials: F
authors.lastname: Herranz-Trillo
authors.affiliation: Joint BSC-CRG-IRB Research Program in Computational Biology, Barcelona Supercomputing Center, Jordi Girona 31, 08034, Barcelona, Spain.
authors.forename: Martin
authors.initials: M
authors.lastname: Kotev
authors.affiliation: NMR Facility, Scientific and Technological Centers University of Barcelona (CCiTUB), Baldiri Reixac 10, 08028, Barcelona, Spain.
authors.forename: Margarida
authors.initials: M
authors.lastname: Gairí
authors.affiliation: Joint BSC-CRG-IRB Research Program in Computational Biology, Barcelona Supercomputing Center, Jordi Girona 31, 08034, Barcelona, Spain.|Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluís Companys 23, 08010, Barcelona, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Guallar
authors.affiliation: Centre de Biochimie Structurale, INSERM U1054, CNRS UMR 5048, Université de Montpellier 1 and 2, 29 rue de Navacelles, 34090, Montpellier, France.
authors.forename: Pau
authors.initials: P
authors.lastname: Bernadó
authors.affiliation: Structural Biology Unit, CIC bioGUNE, Parque Tecnológico de Vizcaya, Ed. 800, 48160, Derio, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Millet
authors.affiliation: Chemistry and Molecular Pharmacology Program, Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028, Barcelona, Spain.|Iproteos, S L, Barcelona Science Park, Baldiri Reixac 10, 08028, Barcelona, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Tarragó
authors.affiliation: Chemistry and Molecular Pharmacology Program, Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028, Barcelona, Spain. ernest.giralt@irbbarcelona.org.|Department of Organic Chemistry, University of Barcelona, Martí i Franquès, 1-11, 08028, Barcelona, Spain. ernest.giralt@irbbarcelona.org.
authors.forename: Ernest
authors.initials: E
authors.lastname: Giralt
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D000085822:Prolyl Oligopeptidases; D054730:Protein Interaction Domains and Motifs; D053838:Scattering, Small Angle; D012697:Serine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D013552:Swine; D014961:X-Ray Diffraction
chemical_list: D004791:Enzyme Inhibitors; D012697:Serine Endopeptidases; C000705287:PREPL protein, human; D000085822:Prolyl Oligopeptidases
keywords: NMR spectroscopy; SAXS; prolyl oligopeptidase; protein dynamics; protein-protein interactions