School of Chemistry, University of Wollongong , Northfields Avenue, Wollongong 2522, NSW, Australia.
J Med Chem. 2013 Nov 14;56(21):8665-73. doi: 10.1021/jm401118f. Epub 2013 Oct 22.
Protein-protein interactions based on linear motif (LM) recognition play roles in many cell regulatory processes. The E. coli sliding clamp is a protein mediator of replisome formation, which uses a common surface pocket composed of two subsites (I and II) to interact with LMs in multiple binding partners. A structural and thermodynamic dissection of sliding clamp-LM recognition has been performed, providing support for a sequential binding model. According to the model, a hydrophobic C-terminal LM dipeptide submotif acts as an anchor to establish initial contacts within subsite I, and this is followed by formation of a stabilizing hydrogen-bonding network between the flanking LM residues and subsite II. Differential solvation/desolvation during positioning of the submotifs is proposed as a driver for the sequential binding. Our model provides general insights into linear motif recognition and should guide the design of small-molecule inhibitors of the E. coli sliding clamp, an emerging antibacterial target.
基于线性基序 (LM) 识别的蛋白质-蛋白质相互作用在许多细胞调控过程中发挥作用。大肠杆菌滑动夹是复制体形成的蛋白质介体，它使用由两个亚基 (I 和 II) 组成的常见表面口袋与多个结合伴侣中的 LM 相互作用。已经对滑动夹-LM 识别进行了结构和热力学剖析，为顺序结合模型提供了支持。根据该模型，疏水性 C 末端 LM 二肽亚基作为锚定点，在亚基 I 内建立初始接触，随后在侧翼 LM 残基和亚基 II 之间形成稳定的氢键网络。在亚基定位过程中，不同的溶剂化/去溶剂化被提出作为顺序结合的驱动力。我们的模型为线性基序识别提供了一般性的见解，并应指导大肠杆菌滑动夹的小分子抑制剂的设计，大肠杆菌滑动夹是一个新兴的抗菌靶标。
