{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T17:49:22Z","timestamp":1791308962814,"version":"4.3.1"},"reference-count":42,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2013,6,26]],"date-time":"2013-06-26T00:00:00Z","timestamp":1372204800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"National Science Foundation","award":["MCB 01110741 (EHS)"],"award-info":[{"award-number":["MCB 01110741 (EHS)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Protein Science"],"published-print":{"date-parts":[[2013,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Aminoglycoside\u2010modifying enzymes (AGMEs) are expressed in many pathogenic bacteria and cause resistance to aminoglycoside (AG) antibiotics. Remarkably, the substrate promiscuity of AGMEs is quite variable. The molecular basis for such ligand promiscuity is largely unknown as there is not an obvious link between amino acid sequence or structure and the antibiotic profiles of AGMEs. To address this issue, this article presents the first kinetic and thermodynamic characterization of one of the least promiscuous AGMEs, the AG <jats:italic>N<\/jats:italic>3 acetyltransferase\u2010IIa (AAC\u2010IIa) and its comparison to two highly promiscuous AGMEs, the AG <jats:italic>N<\/jats:italic>3\u2010acetyltransferase\u2010IIIb (AAC\u2010IIIb) and the AG phosphotransferase(3\u2032)\u2010IIIa (APH). Despite having similar antibiotic selectivities, AAC\u2010IIIb and APH catalyze different reactions and share no homology to one another. AAC\u2010IIa and AAC\u2010IIIb catalyze the same reaction and are very similar in both amino acid sequence and structure. However, they demonstrate strong differences in their substrate profiles and kinetic and thermodynamic properties. AAC\u2010IIa and APH are also polar opposites in terms of ligand promiscuity but share no sequence or apparent structural homology. However, they both are highly dynamic and may even contain disordered segments and both adopt well\u2010defined conformations when AGs are bound. Contrary to this AAC\u2010IIIb maintains a well\u2010defined structure even in apo form. Data presented herein suggest that the antibiotic promiscuity of AGMEs may be determined neither by the flexibility of the protein nor the size of the active site cavity alone but strongly modulated or controlled by the effects of the cosubstrate on the dynamic and thermodynamic properties of the enzyme.<\/jats:p>","DOI":"10.1002\/pro.2273","type":"journal-article","created":{"date-parts":[[2013,5,2]],"date-time":"2013-05-02T21:08:05Z","timestamp":1367528885000},"page":"916-928","source":"Crossref","is-referenced-by-count":21,"title":["Ligand promiscuity through the eyes of the aminoglycoside <i>N<\/i>3 acetyltransferase IIa"],"prefix":"10.1002","volume":"22","author":[{"given":"Adrianne L.","family":"Norris","sequence":"first","affiliation":[{"name":"From the Department of Biochemistry and Cellular and Molecular Biology The University of Tennessee Knoxville Tennessee 37996"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Engin H.","family":"Serpersu","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry and Cellular and Molecular Biology The University of Tennessee Knoxville Tennessee 37996"},{"name":"Graduate School of Genome Science and Technology University of Tennessee and Oak Ridge National Laboratories Knoxville Tennessee 37996"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2013,6,26]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1128\/mr.57.1.138-163.1993","article-title":"Molecular\u2010genetics of aminoglycoside resistance genes and familial relationships of the aminoglycoside\u2010modifying enzymes","volume":"57","author":"Shaw KJ","year":"1993","journal-title":"Microbiol Rev"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/192633a0"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/327389a0"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi00188a024"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkp180"},{"key":"e_1_2_7_7_1","first-page":"651","article-title":"Tuberculosis treatment for the beginning of the next century","volume":"3","author":"Schraufnagel DE","year":"1999","journal-title":"Intl J Tuberculosis Lung Dis"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja901685h"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi1001568"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi2011916"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja0643220"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi701711j"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi0487286"},{"key":"e_1_2_7_14_1","first-page":"691","volume-title":"Antibiotics in Laboratory Medicine","author":"Davies JE","year":"1991"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi020190l"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi301126g"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi100155j"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi060935d"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00332949"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.32.12.1834"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/28.3.333"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.33.8.1153"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biophys.29.1.81"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-396527-1.00005-X"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2011.03.061"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biophys.093008.131258"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sbi.2010.10.007"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi201008f"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.bb.19.060190.001111"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.24163"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200501399"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm060732n"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/nsb830"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.7164\/antibiotics.32.1147"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi0261241"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/bip.21251"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0003-2697(03)00289-6"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(00)76713-0"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi00708a022"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(96)79403-1"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja00052a088"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja982649y"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00197809"}],"container-title":["Protein Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fpro.2273","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fpro.2273","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pro.2273","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,15]],"date-time":"2023-09-15T04:09:53Z","timestamp":1694750993000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/pro.2273"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,6,26]]},"references-count":42,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2013,7]]}},"alternative-id":["10.1002\/pro.2273"],"URL":"https:\/\/doi.org\/10.1002\/pro.2273","archive":["Portico"],"relation":{},"ISSN":["0961-8368","1469-896X"],"issn-type":[{"value":"0961-8368","type":"print"},{"value":"1469-896X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,6,26]]}}}