Three-dimensional Structure of MecI
Three-dimensional Structure of MecI
复制标题
MecI的三维结构
DOI：
--
复制
发表时间：
2003
影响因子：
4.8
通讯作者：
F. Gomis
中科院分区：
文献类型：
--
作者：
R. García;A. Marrero;G. Mallorquí;J. Potempa;M. Coll;F. Gomis
耐甲氧西林金黄色葡萄球菌是影响全球数百万人的医院和社区感染的主要原因。由于获得了使抗生素耐药的分子机制，一些耐甲氧西林的金黄色葡萄球菌感染已经变得基本上无法用β-内酰胺类药物治疗。逃避甲氧西林挑战主要是通过合成一种对抗生素低亲和力的青霉素结合蛋白MecA，当这些蛋白被抗生素灭活时，它会在细胞壁的周转中取代常规的青霉素结合蛋白。MecA的合成受一个信号转导系统的调控，该信号转导系统由传感器/转导分子MecR1和14 kDa转录抑制因子MecI(也称为甲氧西林抑制因子)组成，后者结构性地阻断MecA的转录。MecI的三维结构揭示了两个独立的有翼螺旋结构域的二聚体，每个结构域结合了一个回文DNA操纵子半个位点，以及两个由疏水核心连接在一起的紧密缠绕的新型螺旋阶梯结构的二聚结构域。同源MecR1在二聚化结构域内的有限蛋白水解性切割导致二聚体相互作用表面的丧失、解离和抑制物的释放，从而触发MecA的合成。关于MecA调控途径成分的结构信息，特别是甲氧西林抑制因子，是mecA编码的甲氧西林耐药性的最终转录触发因子，有望导致新的抗菌药物的开发。
Methicillin-resistant Staphylococcus aureus is the main cause of nosocomial and community-onset infections that affect millions of people worldwide. Some methicillin-resistant Staphylococcus aureus infections have become essentially untreatable by β-lactams because of acquired molecular machineries enabling antibiotic resistance. Evasion from methicillin challenge is mainly achieved by the synthesis of a penicillin-binding protein of low affinity for antibiotics, MecA, that replaces regular penicillin-binding proteins in cell wall turnover when these have been inactivated by antibiotics. MecA synthesis is regulated by a signal transduction system consisting of the sensor/transducer MecR1 and the 14-kDa transcriptional repressor MecI (also known as methicillin repressor) that constitutively blocks mecA transcription. The three-dimensional structure of MecI reveals a dimer of two independent winged helix domains, each of which binds a palindromic DNA-operator half site, and two intimately intertwining dimerization domains of novel spiral staircase architecture, held together by a hydrophobic core. Limited proteolytic cleavage by cognate MecR1 within the dimerization domains results in loss of dimer interaction surface, dissociation, and repressor release, which triggers MecA synthesis. Structural information on components of the MecA regulatory pathway, in particular on methicillin repressor, the ultimate transcriptional trigger of mecA-encoded methicillin resistance, is expected to lead to the development of new antimicrobial drugs.