Structural and Thermodynamic Dissection of Linear Motif Recognition by the E. coli Sliding Clamp

作者：Yin Zhou; Kelso Michael J; Beck Jennifer L; Oakley Aaron J^*

来源：Journal of Medicinal Chemistry, 2013, 56(21): 8665-8673.

DOI：10.1021/jm401118f

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.

• 出版日期2013-11-14