{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T22:17:35Z","timestamp":1772662655727,"version":"3.50.1"},"reference-count":27,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2011,5,1]],"date-time":"2011-05-01T00:00:00Z","timestamp":1304208000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2011,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Among Gram-negative bacteria, resistance to \u03b2-lactams is mediated primarily by \u03b2-lactamases (EC 3.2.6.5), periplasmic enzymes that inactivate \u03b2-lactam antibiotics. Substitutions at critical amino acid positions in the class A \u03b2-lactamase families result in enzymes that can hydrolyze extended-spectrum cephalosporins, thus demonstrating an \u201cextended-spectrum\u201d \u03b2-lactamase (ESBL) phenotype. Using SHV ESBLs with substitutions in the \u03a9 loop (R164H and R164S) as target enzymes to understand this enhanced biochemical capability and to serve as a basis for novel \u03b2-lactamase inhibitor development, we determined the spectra of activity and crystal structures of these variants. We also studied the inactivation of the R164H and R164S mutants with tazobactam and SA2-13, a unique \u03b2-lactamase inhibitor that undergoes a distinctive reaction chemistry in the active site. We noted that the reduced\n            <jats:italic>\n              K\n              <jats:sub>i<\/jats:sub>\n            <\/jats:italic>\n            values for the R164H and R164S mutants with SA2-13 are comparable to those with tazobactam (submicromolar). The apo enzyme crystal structures of the R164H and R164S SHV variants revealed an ordered \u03a9 loop architecture that became disordered when SA2-13 was bound. Important structural alterations that result from the binding of SA2-13 explain the enhanced susceptibility of these ESBL enzymes to this inhibitor and highlight ligand-dependent \u03a9 loop flexibility as a mechanism for accommodating and hydrolyzing \u03b2-lactam substrates.\n          <\/jats:p>","DOI":"10.1128\/aac.01360-10","type":"journal-article","created":{"date-parts":[[2011,3,1]],"date-time":"2011-03-01T23:32:24Z","timestamp":1299022344000},"page":"2303-2309","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":26,"title":["Ligand-Dependent Disorder of the \u03a9 Loop Observed in Extended-Spectrum SHV-Type \u03b2-Lactamase"],"prefix":"10.1128","volume":"55","author":[{"given":"Jared M.","family":"Sampson","sequence":"first","affiliation":[{"name":"Departments of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Ke","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher R.","family":"Bethel","sequence":"additional","affiliation":[{"name":"Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S. R. R.","family":"Pagadala","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Southern Methodist University, Dallas, Texas"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael D.","family":"Nottingham","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Southern Methodist University, Dallas, Texas"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert A.","family":"Bonomo","sequence":"additional","affiliation":[{"name":"Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio"},{"name":"Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio"},{"name":"Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John D.","family":"Buynak","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Southern Methodist University, Dallas, Texas"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Focco","family":"van den Akker","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-1097(97)00196-1"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2006.05.005"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-1097(97)00210-3"},{"key":"e_1_3_2_5_2","unstructured":"BushK.\nJacobyG.. 2003. Resistant TEM and SHV \u03b2-lactamases. The Lahey Clinic Burlington MA. http:\/\/www.lahey.org\/studies\/."},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi9908787"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkh395"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2010.04.062"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444904019158"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr030102i"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/45.1.101"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M306059200"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M207271200"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00103a017"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0167-4838(01)00164-9"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.44.6.1725-1727.2000"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi990136d"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/163.2.457"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj3300581"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi034986b"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(97)76066-X"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi035985m"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja063715w"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.18.4.657-686.2005"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.41.3.647"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444904011679"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2836(02)00400-X"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(03)74014-2"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.01360-10","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.01360-10","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T23:29:55Z","timestamp":1645486195000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.01360-10"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,5]]},"references-count":27,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2011,5]]}},"alternative-id":["10.1128\/AAC.01360-10"],"URL":"https:\/\/doi.org\/10.1128\/aac.01360-10","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,5]]},"assertion":[{"value":"2010-10-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2011-02-20","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2011-04-28","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}