title: Protein Tunnels: The Case of Urease Accessory Proteins.
abstract: Transition metals are both essential micronutrients and limited in environmental availability. The Ni(II)-dependent urease protein, the most efficient enzyme known to date, is a paradigm for studying the strategies that cells use to handle an essential, yet toxic, metal ion. Urease is a virulence factor of several human pathogens, in addition to decreasing the efficiency of soil organic nitrogen fertilization. Ni(II) insertion in the urease active site is performed through the action of three essential accessory proteins: UreD, UreF, and UreG. The crystal structure of the UreD-UreF-UreG complex from the human pathogen Helicobacter pylori (HpUreDFG) revealed the presence of tunnels that cross the entire length of both UreF and UreD, potentially able to deliver Ni(II) ions from UreG to apo-urease. Atomistic molecular dynamics simulations performed on the HpUreDFG complex in explicit solvent and at physiological ionic conditions demonstrate the stability of these protein tunnels in solution and provide insights on the trafficking of water molecules inside the tunnels. The presence of different alternative routes across the identified tunnels for Ni(II) ions, water molecules, and carbonate ions, all involved in urease activation, is highlighted here, and their potential role in the urease activation mechanism is discussed.
authors.affiliation: Laboratory of Bioinorganic Chemistry, Department of Pharmacy and Biotechnology, University of Bologna , Viale G. Fanin 40, I-40127 Bologna, Italy.
authors.forename: Francesco
authors.identifier: http://orcid.org/0000-0003-0200-1712
authors.initials: F
authors.lastname: Musiani
authors.affiliation: Laboratory of Computational Medicinal Chemistry, Department of Pharmacy and Biotechnology, University of Bologna , Via Belmeloro 6, I-40126 Bologna, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Gioia
authors.affiliation: Laboratory of Computational Medicinal Chemistry, Department of Pharmacy and Biotechnology, University of Bologna , Via Belmeloro 6, I-40126 Bologna, Italy.
authors.forename: Matteo
authors.identifier: http://orcid.org/0000-0002-3757-7802
authors.initials: M
authors.lastname: Masetti
authors.affiliation: Compunet, Istituto Italiano di Tecnologia , Via Morego 30, I-16163 Genova, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Falchi
authors.affiliation: Laboratory of Computational Medicinal Chemistry, Department of Pharmacy and Biotechnology, University of Bologna , Via Belmeloro 6, I-40126 Bologna, Italy.|Compunet, Istituto Italiano di Tecnologia , Via Morego 30, I-16163 Genova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalli
authors.affiliation: Laboratory of Computational Medicinal Chemistry, Department of Pharmacy and Biotechnology, University of Bologna , Via Belmeloro 6, I-40126 Bologna, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Recanatini
authors.affiliation: Laboratory of Bioinorganic Chemistry, Department of Pharmacy and Biotechnology, University of Bologna , Viale G. Fanin 40, I-40127 Bologna, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Ciurli
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry*; D002352:Carrier Proteins / Q000737:chemistry*; D020134:Catalytic Domain; D016481:Helicobacter Infections / Q000382:microbiology; D016480:Helicobacter pylori / Q000737:chemistry*; D006801:Humans; D007477:Ions / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D009532:Nickel / Q000737:chemistry; D028044:Phosphate-Binding Proteins; D011487:Protein Conformation; D014510:Urease / Q000737:chemistry*; D014867:Water / Q000737:chemistry
chemical_list: D001426:Bacterial Proteins; D002352:Carrier Proteins; D007477:Ions; D028044:Phosphate-Binding Proteins; C086767:UreD protein, Bacteria; C101639:UreF protein, bacteria; C082270:ureG protein, Bacteria; D014867:Water; D009532:Nickel; D014510:Urease