The role of the jaw subdomain of peptidoglycan glycosyltransferases for lipid II polymerization.
The role of the jaw subdomain of peptidoglycan glycosyltransferases for lipid II polymerization.
复制标题
DOI：
10.1016/j.tcsw.2018.06.002
复制
发表时间：
2018-06
期刊：
影响因子：
--
通讯作者：
Roper DI
中科院分区：
文献类型：
--
作者：
Punekar AS;Samsudin F;Lloyd AJ;Dowson CG;Scott DJ;Khalid S;Roper DI
细菌肽聚糖糖基转移酶（PGT）催化脂质II聚合成肽聚糖生物合成所需的线性聚糖链。PGT结构域由一个较大的头部亚域和一个较小的下颌亚域组成，可以被抗生素莫诺霉素a （MoeA）有效抑制。我们展示了与MoeA结合的金黄色葡萄球菌单功能PGT酶的x射线结构，揭示了与颌骨亚域以及PGT供体位点结合的第二个MoeA的电子密度。等温滴定量热法证实了两个具有明显不同亲和力和正协同性的药物结合位点。疏水聚类分析表明，颌骨亚域的膜相互作用表面具有类似于两亲性阳离子-螺旋抗菌肽的结构和物理化学性质，用于脂质II的识别和结合。此外，该酶的无药和结合形式的分子动力学模拟证明了下颌亚结构域运动对脂质II选择和聚合过程的重要性，并为pgt生物合成肽聚糖的机制提供了分子水平的见解。
Bacterial peptidoglycan glycosyltransferases (PGT) catalyse the essential polymerization of lipid II into linear glycan chains required for peptidoglycan biosynthesis. The PGT domain is composed of a large head subdomain and a smaller jaw subdomain and can be potently inhibited by the antibiotic moenomycin A (MoeA). We present an X-ray structure of the MoeA-bound Staphylococcus aureus monofunctional PGT enzyme, revealing electron density for a second MoeA bound to the jaw subdomain as well as the PGT donor site. Isothermal titration calorimetry confirms two drug-binding sites with markedly different affinities and positive cooperativity. Hydrophobic cluster analysis suggests that the membrane-interacting surface of the jaw subdomain has structural and physicochemical properties similar to amphipathic cationic -helical antimicrobial peptides for lipid II recognition and binding. Furthermore, molecular dynamics simulations of the drug-free and -bound forms of the enzyme demonstrate the importance of the jaw subdomain movement for lipid II selection and polymerization process and provide molecular-level insights into the mechanism of peptidoglycan biosynthesis by PGTs.