{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T04:05:49Z","timestamp":1791173149019,"version":"4.1.0"},"reference-count":41,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2007,6,28]],"date-time":"2007-06-28T00:00:00Z","timestamp":1182988800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Proteins"],"published-print":{"date-parts":[[2007,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>TEM\u20101 is a class A \u03b2\u2010lactamase that contributes to the primary defensive measure used by bacteria to hydrolyze the clinically\u2010relevant \u03b2\u2010lactam antibiotics. Several crystal structures of this enzyme complexed with inhibitors display the active\u2010site residue Tyr105 in an alternate orientation relative to that assigned in the free or in the substrate\u2010bound forms. Thus, the alternate conformation may not be favored in the free enzyme and may be adopted only in the presence of inhibitor. As the residue at position 105 is a determinant of substrate specificity, we sought a better understanding of the relation between its conformation and its function in ligand binding. Here, we perform a molecular dynamics simulated annealing protocol to identify stable orientations adopted by Tyr105 in free TEM\u20101. Our results demonstrate that, in the absence of substrate, structurally validated conformers of Tyr105 predominantly adopt either of the two rotameric orientations observed in the crystal structures. This suggests that adoption of either conformation in the free enzyme is energetically favored and is not strictly promoted by ligand binding. We propose that free TEM\u20101 alternates between these two conformations of Tyr105 and that a dynamically heterogeneous population of both rotamers exists in solution. The conformational change significantly reshapes the active\u2010site cavity and modifies the potential for forming specific ligand contacts. Our results add to the body of evidence suggesting that Tyr105 displays a dynamical behavior resulting in alternate ligand binding modes and are consistent with the lower affinity of TEM\u20101 for cephalosporins relative to penicillins. Proteins 2007. \u00a9 2007 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/prot.21485","type":"journal-article","created":{"date-parts":[[2007,6,28]],"date-time":"2007-06-28T22:16:26Z","timestamp":1183068986000},"page":"340-348","source":"Crossref","is-referenced-by-count":23,"title":["Simulated annealing exploration of an active\u2010site tyrosine in TEM\u20101\u03b2\u2010lactamase suggests the existence of alternate conformations"],"prefix":"10.1002","volume":"69","author":[{"given":"Nicolas","family":"Doucet","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joelle N.","family":"Pelletier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2007,6,28]]},"reference":[{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1093\/clinids\/24.Supplement_1.S19"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.8153624"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/208239a0"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro888"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/84981"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444994014496"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/prot.340160406"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444905014356"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi990758z"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi0502700"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M204212200"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2836(02)00400-X"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/359700a0"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2003.12.068"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsb1001-848"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja9818001"},{"key":"e_1_2_6_18_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi992505b"},{"key":"e_1_2_6_19_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi034242y"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1002\/prot.10058"},{"key":"e_1_2_6_21_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi972501b"},{"key":"e_1_2_6_22_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja0259640"},{"key":"e_1_2_6_23_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M407606200"},{"key":"e_1_2_6_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0134(20000815)40:3<389::AID-PROT50>3.0.CO;2-2"},{"key":"e_1_2_6_25_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1993.1172"},{"key":"e_1_2_6_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsb0896-688"},{"key":"e_1_2_6_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsb0396-290"},{"key":"e_1_2_6_28_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi060414q"},{"key":"e_1_2_6_29_2","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/18.8.1585"},{"key":"e_1_2_6_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpc.2003.09.010"},{"key":"e_1_2_6_31_2","doi-asserted-by":"publisher","DOI":"10.1002\/prot.340050109"},{"key":"e_1_2_6_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1093-3263(02)00123-7"},{"key":"e_1_2_6_33_2","doi-asserted-by":"publisher","DOI":"10.1023\/B:JCAM.0000035186.90683.f2"},{"key":"e_1_2_6_34_2","doi-asserted-by":"publisher","DOI":"10.1002\/prot.10286"},{"key":"e_1_2_6_35_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bti825"},{"key":"e_1_2_6_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/0263-7855(96)00018-5"},{"key":"e_1_2_6_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1093-3263(01)00134-6"},{"key":"e_1_2_6_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(01)75785-2"},{"key":"e_1_2_6_39_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi016077x"},{"key":"e_1_2_6_40_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm050721e"},{"key":"e_1_2_6_41_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja027704o"},{"key":"e_1_2_6_42_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm0493663"}],"container-title":["Proteins: 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