Awuni Yaw, Jiang Shimin, Robinson Robert C, Mu Yuguang
School of Biological Sciences, Nanyang Technological University , 60 Nanyang Drive, Singapore 637551.
Institute of Molecular and Cell Biology , A*STAR, Biopolis, Singapore 138673.
J Phys Chem B. 2016 Sep 22;120(37):9867-74. doi: 10.1021/acs.jpcb.6b05199. Epub 2016 Sep 14.
MreB is an actin-like cytoskeleton protein that plays a vital role in the maintenance of the rod-shaped morphology of many bacteria. S-(3,4-Dichlorobenzyl) isothiourea (A22) is an antibiotic-like small molecule that perturbs the rod cell shape and has been suggested to inhibit MreB by targeting ATP hydrolysis. However, without the elucidation of the structure of the ATP-bound state of MreB in the presence of A22, the mechanism of A22 inhibition is still not clear. Here we apply conventional molecular dynamics simulations to explore the dynamics of the active site of MreB in complex with A22 and different nucleotides. We observe that hydrogen bonding between A22 and the catalytic Glu140 residue is not favored in the ATP-A22-bound state of MreB. Water dynamics analysis in the MreB active site reveals that in the presence of A22 water molecules are able to occupy positions suitable for ATP hydrolysis. Overall, our results are consistent with a mechanism in which A22 affects MreB polymerization/depolymerization dynamics in part through slowing phosphate release rather than by inhibiting ATP hydrolysis. These data can be incorporated in the design/development of the next generation of MreB inhibitors.
MreB是一种肌动蛋白样细胞骨架蛋白，在维持许多细菌的杆状形态中起着至关重要的作用。S-(3,4-二氯苄基)异硫脲(A22)是一种类似抗生素的小分子，它会扰乱杆状细胞的形状，并被认为通过靶向ATP水解来抑制MreB。然而，在没有阐明A22存在时MreB的ATP结合状态结构的情况下，A22抑制的机制仍不清楚。在这里，我们应用传统分子动力学模拟来探索与A22和不同核苷酸结合的MreB活性位点的动力学。我们观察到，在MreB的ATP-A22结合状态下，A22与催化性Glu140残基之间的氢键作用并不有利。MreB活性位点的水动力学分析表明，在A22存在的情况下，水分子能够占据适合ATP水解的位置。总体而言，我们的结果与一种机制一致，即A22部分通过减缓磷酸盐释放而非抑制ATP水解来影响MreB的聚合/解聚动力学。这些数据可用于下一代MreB抑制剂的设计/开发。
