耐黏菌素酶MCR-1催化结构域的结构
Structure of the catalytic domain of the colistin resistance enzyme MCR-1.
作者信息
Stojanoski Vlatko, Sankaran Banumathi, Prasad B V Venkataram, Poirel Laurent, Nordmann Patrice, Palzkill Timothy
机构信息
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.
Department of Pharmacology, Baylor College of Medicine, Houston, TX, 77030, USA.
出版信息
BMC Biol. 2016 Sep 21;14(1):81. doi: 10.1186/s12915-016-0303-0.
BACKGROUND
Due to the paucity of novel antibiotics, colistin has become a last resort antibiotic for treating multidrug resistant bacteria. Colistin acts by binding the lipid A component of lipopolysaccharides and subsequently disrupting the bacterial membrane. The recently identified plasmid-encoded MCR-1 enzyme is the first transmissible colistin resistance determinant and is a cause for concern for the spread of this resistance trait. MCR-1 is a phosphoethanolamine transferase that catalyzes the addition of phosphoethanolamine to lipid A to decrease colistin affinity.
RESULTS
The structure of the catalytic domain of MCR-1 at 1.32 Å reveals the active site is similar to that of related phosphoethanolamine transferases.
CONCLUSIONS
The putative nucleophile for catalysis, threonine 285, is phosphorylated in cMCR-1 and a zinc is present at a conserved site in addition to three zincs more peripherally located in the active site. As noted for catalytic domains of other phosphoethanolamine transferases, binding sites for the lipid A and phosphatidylethanolamine substrates are not apparent in the cMCR-1 structure, suggesting that they are present in the membrane domain.
背景
由于新型抗生素匮乏，黏菌素已成为治疗多重耐药菌的最后一道防线。黏菌素通过结合脂多糖的脂质A成分发挥作用，随后破坏细菌细胞膜。最近发现的质粒编码MCR-1酶是首个可传播的黏菌素耐药决定因素，这种耐药特性的传播令人担忧。MCR-1是一种磷酸乙醇胺转移酶，催化磷酸乙醇胺添加到脂质A上，从而降低黏菌素的亲和力。
结果
MCR-1催化结构域在1.32 Å分辨率下的结构显示，其活性位点与相关磷酸乙醇胺转移酶的活性位点相似。
结论
催化作用的推定亲核试剂苏氨酸285在共价修饰的MCR-1（cMCR-1）中被磷酸化，除了活性位点外围的三个锌外，在一个保守位点还存在一个锌。正如其他磷酸乙醇胺转移酶的催化结构域一样，在cMCR-1结构中，脂质A和磷脂酰乙醇胺底物的结合位点不明显，这表明它们存在于膜结构域中。
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