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It has been shown that tRNA\u2013guanine transglycosylase (TGT) is essential for the pathogenicity of <jats:italic>Shigella flexneri<\/jats:italic>. Herein, the molecular recognition properties of a guanine binding pocket in <jats:italic>Zymomonas mobilis<\/jats:italic> TGT are investigated with a series of <jats:italic>lin<\/jats:italic>\u2010benzohypoxanthine\u2010 and <jats:italic>lin<\/jats:italic>\u2010benzoguanine\u2010based inhibitors that bear substituents to occupy either the ribose\u201033 or the ribose\u201034 pocket. The three inhibitor scaffolds differ by the substituent at C(6) being H, NH<jats:sub>2<\/jats:sub>, or NH\uf8ffalkyl. These differences lead to major changes in the inhibition constants, p<jats:italic>K<\/jats:italic><jats:sub>a<\/jats:sub> values, and binding modes. Compared to the <jats:italic>lin<\/jats:italic>\u2010benzoguanines, with an exocyclic NH<jats:sub>2<\/jats:sub> at C(6), the <jats:italic>lin<\/jats:italic>\u2010benzohypoxanthines without an exocyclic NH<jats:sub>2<\/jats:sub> group have a weaker affinity as several ionic protein\u2013ligand hydrogen bonds are lost. X\u2010ray cocrystal structure analysis reveals that a new water cluster is imported into the space vacated by the lacking NH<jats:sub>2<\/jats:sub> group and by a conformational shift of the side chain of catalytic Asp102. In the presence of an N\u2010alkyl group at C(6) in <jats:italic>lin<\/jats:italic>\u2010benzoguanine ligands, this water cluster is largely maintained but replacement of one of the water molecules in the cluster leads to a substantial loss in binding affinity. This study provides new insight into the role of water clusters at enzyme active sites and their challenging substitution by ligand parts, a topic of general interest in contemporary structure\u2010based drug design.<\/jats:p>","DOI":"10.1002\/chem.201200809","type":"journal-article","created":{"date-parts":[[2012,6,26]],"date-time":"2012-06-26T16:21:47Z","timestamp":1340727707000},"page":"9246-9257","source":"Crossref","is-referenced-by-count":20,"title":["From <i>lin<\/i>\u2010Benzoguanines to <i>lin<\/i>\u2010Benzohypoxanthines as Ligands for <i>Zymomonas mobilis<\/i> tRNA\u2013Guanine Transglycosylase: Replacement of Protein\u2013Ligand Hydrogen Bonding by Importing Water Clusters"],"prefix":"10.1002","volume":"18","author":[{"given":"Luzi Jakob","family":"Barandun","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Florian","family":"Immekus","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philipp C.","family":"Kohler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandro","family":"Tonazzi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bj\u00f6rn","family":"Wagner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Severin","family":"Wendelspiess","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tina","family":"Ritschel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Heine","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manfred","family":"Kansy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerhard","family":"Klebe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fran\u00e7ois","family":"Diederich","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2012,6,26]]},"reference":[{"key":"e_1_2_6_1_2","doi-asserted-by":"crossref","unstructured":"C. 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