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Replacement of Water Molecules in a Phosphate Binding Site by Furanoside‐Appended lin ‐Benzoguanine Ligands of tRNA‐Guanine Transglycosylase (TGT)
Author(s) -
Barandun Luzi J.,
Ehrmann Frederik R.,
Zimmerli Daniel,
Immekus Florian,
Giroud Maude,
Grünenfelder Claudio,
Schweizer W. Bernd,
Bernet Bruno,
Betz Michael,
Heine Andreas,
Klebe Gerhard,
Diederich François
Publication year - 2015
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201405764
Subject(s) - ribose , stereochemistry , guanine , chemistry , transfer rna , moiety , enzyme , binding site , active site , nucleotide , molecule , rna , biochemistry , organic chemistry , gene
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.