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Owing to its importance, this enzyme has been the focus of intensive research since its isolation in the mid-1980s but, despite much effort, structural details of AAC(6\u2032)-Ie-APH(2\u2032\u2032)-Ia have remained elusive. The structure of the Mg<jats:sub>2<\/jats:sub>GDP complex of the APH(2\u2032\u2032)-Ia domain of the bifunctional enzyme has now been determined at 2.3\u2005\u00c5 resolution. The structure of APH(2\u2032\u2032)-Ia is reminiscent of the structures of other aminoglycoside phosphotransferases, having a two-domain architecture with the nucleotide-binding site located at the junction of the two domains. Unlike the previously characterized APH(2\u2032\u2032)-IIa and APH(2\u2032\u2032)-IVa enzymes, which are capable of utilizing both ATP and GTP as the phosphate donors, APH(2\u2032\u2032)-Ia uses GTP exclusively in the phosphorylation of the aminoglycoside antibiotics, and in this regard closely resembles the GTP-dependent APH(2\u2032\u2032)-IIIa enzyme. In APH(2\u2032\u2032)-Ia this GTP selectivity is governed by the presence of a `gatekeeper' residue, Tyr100, the side chain of which projects into the active site and effectively blocks access to the adenine-binding template. Mutation of this tyrosine residue to a less bulky phenylalanine provides better access for ATP to the NTP-binding template and converts APH(2\u2032\u2032)-Ia into a dual-specificity enzyme.<\/jats:p>","DOI":"10.1107\/s1399004714005331","type":"journal-article","created":{"date-parts":[[2014,5,22]],"date-time":"2014-05-22T15:40:37Z","timestamp":1400773237000},"page":"1561-1571","update-policy":"https:\/\/doi.org\/10.1107\/cm_01","source":"Crossref","is-referenced-by-count":9,"title":["Structure of the phosphotransferase domain of the bifunctional aminoglycoside-resistance enzyme AAC(6\u2032)-Ie-APH(2\u2032\u2032)-Ia"],"prefix":"10.1107","volume":"70","author":[{"given":"Clyde A.","family":"Smith","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marta","family":"Toth","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monolekha","family":"Bhattacharya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hilary","family":"Frase","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sergei B.","family":"Vakulenko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"329","published-online":{"date-parts":[[2014,5,23]]},"reference":[{"key":"be5260_bb1","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1107\/S0907444909052925","volume":"66","author":"Adams","year":"2010","journal-title":"Acta Cryst. 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