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Mol. Biosci."],"abstract":"<jats:p>Despite class A ESBLs carrying substitutions outside catalytic regions, such as Cys69Tyr or Asn136Asp, have emerged as new clinical threats, the molecular mechanisms underlying their acquired antibiotics-hydrolytic activity remains unclear. We discovered that this non-catalytic-region (NCR) mutations induce significant dislocation of \u03b23-\u03b24 strands, conformational changes in critical residues associated with ligand binding to the lid domain, dynamic fluctuation of \u03a9-loop and \u03b23-\u03b24 elements. Such structural changes increase catalytic regions\u2019 flexibility, enlarge active site, and thereby accommodate third-generation cephalosporin antibiotics, ceftazidime (CAZ). Notably, the electrostatic property around the oxyanion hole of Cys69Tyr ESBL is significantly changed, resulting in possible additional stabilization of the acyl-enzyme intermediate. Interestingly, the NCR mutations are as effective for antibiotic resistance by altering the structure and dynamics in regions mediating substrate recognition and binding as single amino-acid substitutions in the catalytic region of the canonical ESBLs. We believe that our findings are crucial in developing successful therapeutic strategies against diverse class A ESBLs, including the new NCR-ESBLs.<\/jats:p>","DOI":"10.3389\/fmolb.2020.598998","type":"journal-article","created":{"date-parts":[[2020,11,27]],"date-time":"2020-11-27T06:52:26Z","timestamp":1606459946000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Non-catalytic-Region Mutations Conferring Transition of Class A \u03b2-Lactamases Into ESBLs"],"prefix":"10.3389","volume":"7","author":[{"given":"Thinh-Phat","family":"Cao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyojeong","family":"Yi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Immanuel","family":"Dhanasingh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suparna","family":"Ghosh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin Myung","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun Ho","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seol","family":"Ryu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heenam Stanley","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung Haeng","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2020,11,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2167","DOI":"10.1107\/S0907444913015291","article-title":"Molecular replacement: tricks and treats.","author":"Abergel","year":"2013","journal-title":"Acta Crystallogr. 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