Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, USA.
J Biol Chem. 2011 Sep 9;286(36):31466-72. doi: 10.1074/jbc.M111.252189. Epub 2011 Jul 20.
The integral membrane protein BlaR1 of methicillin-resistant Staphylococcus aureus senses the presence of β-lactam antibiotics in the milieu and transduces the information to the cytoplasm, where the biochemical events that unleash induction of antibiotic resistance mechanisms take place. We report herein by two-dimensional and three-dimensional NMR experiments of the sensor domain of BlaR1 in solution and by determination of an x-ray structure for the apo protein that Lys-392 of the antibiotic-binding site is posttranslationally modified by N(ζ)-carboxylation. Additional crystallographic and NMR data reveal that on acylation of Ser-389 by antibiotics, Lys-392 experiences N(ζ)-decarboxylation. This unique process, termed the lysine N(ζ)-decarboxylation switch, arrests the sensor domain in the activated ("on") state, necessary for signal transduction and all the subsequent biochemical processes. We present structural information on how this receptor activation process takes place, imparting longevity to the antibiotic-receptor complex that is needed for the induction of the antibiotic-resistant phenotype in methicillin-resistant S. aureus.
耐甲氧西林金黄色葡萄球菌的整合膜蛋白 BlaR1 感知环境中β-内酰胺抗生素的存在，并将信息转导至细胞质，在细胞质中发生引发抗生素耐药机制的生化事件。我们通过 BlaR1 传感器结构域在溶液中的二维和三维 NMR 实验以及apo 蛋白的 X 射线结构测定报告，抗生素结合位点的 Lys-392 通过 N(ζ)-羧化作用进行翻译后修饰。额外的晶体学和 NMR 数据表明，在抗生素酰化 Ser-389 时，Lys-392 经历 N(ζ)-脱羧作用。这种独特的过程，称为赖氨酸 N(ζ)-脱羧开关，使传感器结构域处于激活（“开”）状态，这对于信号转导和所有随后的生化过程是必需的。我们提供了有关这种受体激活过程如何发生的结构信息，赋予了抗生素-受体复合物的长寿性，这是诱导耐甲氧西林金黄色葡萄球菌中抗生素耐药表型所必需的。
