Replacement of Water Molecules in a Phosphate Binding Site by Furanoside‐Appended lin‐Benzoguanine Ligands of tRNA‐Guanine Transglycosylase (TGT) |
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| Authors: | Dr. Luzi J. Barandun Frederik R. Ehrmann Daniel Zimmerli Dr. Florian Immekus Maude Giroud Claudio Grünenfelder Dr. W. Bernd Schweizer Dr. Bruno Bernet Michael Betz Prof. Dr. Andreas Heine Prof. Dr. Gerhard Klebe Prof. Dr. François Diederich |
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| Affiliation: | 1. Laboratorium für Organische Chemie, ETH Zürich, Vladimir‐Prelog‐Weg 3, HCI, 8093 Zürich (Switzerland), Fax: (+41)?44‐632‐1109;2. Institut für Pharmazeutische Chemie, Philipps‐Universit?t Marburg, Marbacher Weg 6, 35032 Marburg (Germany), Fax: (+49)?6421‐282‐8994;3. F. Hoffmann‐La Roche Ltd, Discovery Technologies, Bldg 92/5.64C, 4070 Basel (Switzerland) |
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| 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. |
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| Keywords: | molecular recognition phosphate binding sites shigellosis structure‐based design water cluster |
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