title: Replacement of water molecules in a phosphate binding site by furanoside-appended lin-benzoguanine ligands of tRNA-guanine transglycosylase (TGT).
abstract: The enzyme tRNA-guanine transglycosylase has been identified as a drug target for the foodborne illness shigellosis. A key challenge in structure-based design for this enzyme is the filling of the polar ribose-34 pocket. Herein, we describe a novel series of ligands consisting of furanoside-appended lin-benzoguanines. They were designed to replace a conserved water cluster and differ by the functional groups at C(2) and C(3) of the furanosyl moiety being either OH or OMe. The unfavorable desolvation of Asp102 and Asp280, which are located close to the ribose-34 pocket, had a significant impact on binding affinity. While the enzyme has tRNA as its natural substrate, X-ray co-crystal structures revealed that the furanosyl moieties of the ligands are not accommodated in the tRNA ribose-34 site, but at the location of the adjacent phosphate group. A remarkable similarity of the position of the oxygen atoms in these two structures suggests furanosides as a potential phosphate isoster.
authors.affiliation: Laboratorium für Organische Chemie, ETH Zürich, Vladimir-Prelog-Weg 3, HCI, 8093 Zürich (Switzerland), Fax: (+41) 44-632-1109.
authors.forename: Luzi J
authors.initials: LJ
authors.lastname: Barandun
authors.forename: Frederik R
authors.initials: FR
authors.lastname: Ehrmann
authors.forename: Daniel
authors.initials: D
authors.lastname: Zimmerli
authors.forename: Florian
authors.initials: F
authors.lastname: Immekus
authors.forename: Maude
authors.initials: M
authors.lastname: Giroud
authors.forename: Claudio
authors.initials: C
authors.lastname: Grünenfelder
authors.forename: W Bernd
authors.initials: WB
authors.lastname: Schweizer
authors.forename: Bruno
authors.initials: B
authors.lastname: Bernet
authors.forename: Michael
authors.initials: M
authors.lastname: Betz
authors.forename: Andreas
authors.initials: A
authors.lastname: Heine
authors.forename: Gerhard
authors.initials: G
authors.lastname: Klebe
authors.forename: François
authors.initials: F
authors.lastname: Diederich
mesh_terms: D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D006147:Guanine / Q000737:chemistry / Q000378:metabolism*; D008024:Ligands; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D010430:Pentosyltransferases / Q000737:chemistry / Q000378:metabolism*; D010710:Phosphates / Q000737:chemistry / Q000378:metabolism*; D014867:Water / Q000737:chemistry*; D017355:Zymomonas / Q000201:enzymology
chemical_list: D001562:Benzimidazoles; D008024:Ligands; D010710:Phosphates; D014867:Water; D006147:Guanine; D010430:Pentosyltransferases; C020837:queuine tRNA-ribosyltransferase
keywords: molecular recognition; phosphate binding sites; shigellosis; structure-based design; water cluster