Details

Autor(en) / Beteiligte

• 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

Titel

Replacement of Water Molecules in a Phosphate Binding Site by Furanoside-Appended lin-Benzoguanine Ligands of tRNA-Guanine Transglycosylase (TGT)

Ist Teil von

• Chemistry : a European journal, 2015-01, Vol.21 (1), p.126-135

Ort / Verlag

Weinheim: WILEY-VCH Verlag

Erscheinungsjahr

2015

Link zum Volltext

Quelle

Wiley Online Library All Journals

Beschreibungen/Notizen

• 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. Phosphate binding sites: Furanoside‐appended lin‐benzoguanines are investigated as a replacement for a water cluster in the polar ribose‐34 pocket of the enzyme tRNA‐guanine transglycosylase (see figure), which has been identified as a drug target for the treatment of Shigellosis. Based on X‐ray co‐crystal structures, it is proposed that furanosides are suitable groups to fill phosphate binding sites.