title: Structural analysis of Pla protein from the biological warfare agent Yersinia pestis: docking and molecular dynamics of interactions with the mammalian plasminogen system.
abstract: Yersinia pestis protein Pla is a plasmid-coded outer membrane protein with aspartic-protease activity. Pla exhibits a plasminogen (Plg) activator activity (PAA) that promotes the cleavage of Plg to the active serine-protease form called plasmin. Exactly how Pla activates Plg into plasmin remains unclear. To investigate this event, we performed the interactions between the predicted Plg and Pla protein structures by rigid-body docking with the HEX program and evaluated the complex stability by molecular dynamics (MD) using the GROMACS package programs. The predicted docked complex of Plg-Pla shows the same interaction site predicted by experimental site-direct mutagenesis in other studies. After a total of 8 ns of MD simulation, we observed the relaxation of the beta-barrel structure of Pla and the progressive approximation and stabilization between the cleavage site of Plg into the extracellular loops of Pla, followed by the increase in the number of H bonds. We also report here the aminoacids that participate in the active site and the sub sites of interaction. The total understanding of these interactions can be an important tool for drug design against bacterial proteases.
authors.affiliation: Laboratory of Molecular Modeling and Dynamics , Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. eruback@biof.ufrj.br
authors.forename: Eduardo
authors.initials: E
authors.lastname: Ruback
authors.forename: Leandro Araujo
authors.initials: LA
authors.lastname: Lobo
authors.forename: Tanos Celmar Costa
authors.initials: TC
authors.lastname: França
authors.forename: Pedro Geraldo
authors.initials: PG
authors.lastname: Pascutti
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D010958:Plasminogen / Q000737:chemistry*; D010960:Plasminogen Activators / Q000737:chemistry*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055550:Protein Stability; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017386:Sequence Homology, Amino Acid; D040681:Structural Homology, Protein; D015010:Yersinia pestis / Q000201:enzymology*
chemical_list: D001426:Bacterial Proteins; D010958:Plasminogen; C078140:Pla protease, Yersinia pestis; D010960:Plasminogen Activators