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Structural and thermodynamic dissection of linear motif recognition by the E. coli sliding clamp

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posted on 2024-11-16, 02:04 authored by Zhou Yin, Michael Kelso, Jennifer BeckJennifer Beck, Aaron OakleyAaron Oakley
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.

Funding

Fragment-based screening approaches for new antibiotics directed against the bacterial sliding clamp

Australian Research Council

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Fragment Based Screening for new Antibiotics by Protein X-Ray Crystallography

Australian Research Council

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History

Citation

Yin, Z., Kelso, M. J., Beck, J. L. & Oakley, A. J. (2013). Structural and thermodynamic dissection of linear motif recognition by the E. coli sliding clamp. Journal of Medicinal Chemistry, 56 (21), 8665-8673.

Journal title

Journal of Medicinal Chemistry

Volume

56

Issue

21

Pagination

8665-8673

Language

English

RIS ID

83278

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