title: Variations in periplasmic loop interactions determine the pH-dependent activity of the hexameric urea transporter UreI from Helicobacter pylori: a molecular dynamics study.
abstract: BACKGROUND
  Helicobacter pylori is an important factor in the development of diseases such as ulcer and gastric cancer. This bacterium uses a periplasmic transporter, UreI, to deliver urea to the intracelullar space, where later it is transformed into ammonia by the cytoplasmic enzyme urease to survive the acidic condition of the human stomach. The UreI transporter presents a pH-dependent activity, where this pH-dependence remains unknown at a structural level. Althought the existance of several protonable residues in the periplasmic loops are related to the pH-dependent activity, we find interesting to have a clear view of the conformational changes involved in this phenomena through a molecular dynamic study.
  
  
  RESULTS
  Molecular dynamic simulations of the UreI transporter at three different pH conditions were performed, revealing two main pH-dependent conformations, which we present as the open and close states. We find that salt bridges between the periplasmic loops are crucial interactions that stabilize these conformations. Besides, a cooperative behaviour exists between the six subunits of the system that is necessary to fulfill the activity of this transporter.
  
  
  CONCLUSIONS
  We found different pH-dependent conformations of the urea transporter UreI from Helicobacter pylori, which are related to salt-bridge interactions in the periplasmic regions. The behaviour of every channel in the system is not independent, given the existance of a cooperative behaviour through the formation of salt-bridges between the subunits of the hexameric system. We believe that our results will be related to the generation of new eradication therapies using this transporter as an attractive target, denoting that the knowledge of the possible pH-dependent conformations adopted for this transporter are important for the development of rational drug design approximations.
authors.affiliation: Department of Pharmacology, School of Sciences, University of Concepción, Concepción, Chile. jcdelpiano@gmail.com.
authors.forename: Javier
authors.initials: J
authors.lastname: Cáceres-Delpiano
authors.affiliation: Department of Pharmacology, School of Sciences, University of Concepción, Concepción, Chile. jteneb@udec.cl.
authors.forename: Jaime
authors.initials: J
authors.lastname: Teneb
authors.affiliation: Department of Pharmacology, School of Sciences, University of Concepción, Concepción, Chile. romansilla@udec.cl.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Mansilla
authors.affiliation: Department of Microbiology, School of Sciences, University of Concepción, Concepción, Chile. apgarcia@udec.cl.
authors.forename: Apolinaria
authors.initials: A
authors.lastname: García
authors.affiliation: Department of Pharmacology, School of Sciences, University of Concepción, Concepción, Chile. alsalas@udec.cl.
authors.forename: Alexis
authors.initials: A
authors.lastname: Salas-Burgos
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry*; D016480:Helicobacter pylori / Q000737:chemistry / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D026901:Membrane Transport Proteins / Q000737:chemistry*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D019897:Periplasm / Q000378:metabolism; D011487:Protein Conformation; D012492:Salts
chemical_list: D001426:Bacterial Proteins; D026901:Membrane Transport Proteins; D012492:Salts; C114527:UreI protein, Helicobacter pylori