{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T08:04:07Z","timestamp":1789200247564,"version":"build-2803163510"},"reference-count":41,"publisher":"National Academy of Sciences","issue":"1","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2001,1,2]]},"abstract":"<jats:p>In Gram-negative bacteria, TEM-1 \u03b2-lactamase provides the major\n mechanism of plasmid-mediated \u03b2-lactam resistance. Natural variants\n of TEM-1 with increased antibiotic resistance have appeared in response\n to the use of extended-spectrum \u03b2-lactam antibiotics (e.g.,\n ceftazidime) and \u03b2-lactamase inhibitors (e.g., clavulanic acid). Some\n of the variant enzymes are more efficient at catalyzing \u03b2-lactam\n hydrolysis, whereas others are more resistant to inhibitors. M182T is a\n substitution observed in both types of variant TEM-1 \u03b2-lactamases.\n This mutation is found only in combination with other amino acid\n substitutions, suggesting that it may correct defects introduced by\n other mutations that alter the specificity. An engineered core\n mutation, L76N, which diminishes the periplasmic \u03b2-lactamase activity\n by 100-fold, was used as a model to understand the mechanism of\n suppression of the M182T mutation. Biochemical studies of the L76N\n enzyme alone and in combination with the M182T mutation indicate that\n the M182T substitution acts at the level of folding but does not affect\n the thermodynamic stability of TEM-1 \u03b2-lactamase. Thus, the M182T\n substitution is an example of a naturally occurring mutation that has\n evolved to alter the folding pathway of a protein and confer a\n selective advantage during the evolution of drug resistance.<\/jats:p>","DOI":"10.1073\/pnas.98.1.283","type":"journal-article","created":{"date-parts":[[2012,7,30]],"date-time":"2012-07-30T13:19:48Z","timestamp":1343654388000},"page":"283-288","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":41,"title":["A secondary drug resistance mutation of TEM-1 \u03b2-lactamase that suppresses misfolding and aggregation"],"prefix":"10.1073","volume":"98","author":[{"given":"Vera","family":"Sideraki","sequence":"first","affiliation":[{"name":"Verna and Marrs McLean Department of Biochemistry and Molecular\r Biology and Department of Molecular Virology and\r Microbiology, Baylor College of Medicine, Houston, TX 77030"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanzhi","family":"Huang","sequence":"additional","affiliation":[{"name":"Verna and Marrs McLean Department of Biochemistry and Molecular\r Biology and Department of Molecular Virology and\r Microbiology, Baylor College of Medicine, Houston, TX 77030"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"Palzkill","sequence":"additional","affiliation":[{"name":"Verna and Marrs McLean Department of Biochemistry and Molecular\r Biology and Department of Molecular Virology and\r Microbiology, Baylor College of Medicine, Houston, TX 77030"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiram F.","family":"Gilbert","sequence":"additional","affiliation":[{"name":"Verna and Marrs McLean Department of Biochemistry and Molecular\r Biology and Department of Molecular Virology and\r Microbiology, Baylor College of Medicine, Houston, TX 77030"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2000,12,12]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.8153624"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/374569a0"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00004a007"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/374494a0"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/0966-842X(94)90611-4"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/359700a0"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.35.9.1697"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/43.4.447"},{"key":"e_1_3_3_9_2","first-page":"203","volume":"134","author":"Arlet G","year":"1995","unstructured":"G Arlet, G Brami, D Decre, A Flippo, O Gaillot, P H Lagrange, A Philippon FEMS Microbiol Lett 134, 203\u2013208 (1995).","journal-title":"FEMS Microbiol Lett"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/0378-1119(89)90237-0"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)31536-3"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.37.22538"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.41.26603"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.2.781"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.39.11.2478"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.43.4.969"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.37.10.2059"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.42.7.1671"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.42.1.108"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.44.9.2537-2539.2000"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.16.8801"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/123.3.441"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1002\/prot.340160406"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1996.0279"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)97200-5"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.1.4.283"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/0003-2697(76)90527-3"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.1994.tb01011.x"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/prot.340220204"},{"key":"e_1_3_3_30_2","first-page":"311","volume-title":"Protein Structure","author":"Pace C N","year":"1990","unstructured":"C N Pace, B A Shirley, J A Thomson Protein Structure, ed T E Creighton (Oxford Univ. 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