Structural Basis of Affinity Maturation and Intramolecular Cooperativity in a Protein-Protein Interaction

• DOI: 10.1016/j.str.2005.08.015
• Publication Date: 2005-12-15T18:00:20Z
• Authors: Sangwoo Cho; Chittoor P. Swami...; Jianying Yang; Melissa C. Kerzic; Rongjin Guan; Michele C. Kieke; David M. Kranz; Roy A. Mariuzza; Eric J. Sundberg
• Keywords: Models, Molecular; Protein Conformation; Receptors, Antigen, T-Cell, alpha-beta; Water; Crystallography, X-Ray; Peptide Fragments; Enterotoxins; Mice; Amino Acid Substitution; Structural Biology; Mutation; Protein Interaction Mapping; Animals; Molecular Biology

Although protein-protein interactions are involved in nearly all cellular processes, general rules for describing affinity and selectivity in protein-protein complexes are lacking, primarily because correlations between changes in protein structure and binding energetics have not been well determined. Here, we establish the structural basis of affinity maturation for a protein-protein interaction system that we had previously characterized energetically. This model system exhibits a 1500-fold affinity increase. Also, its affinity maturation is restricted by negative intramolecular cooperativity. With three complex and six unliganded variant X-ray crystal structures, we provide molecular snapshots of protein interface remodeling events that span the breadth of the affinity maturation process and present a comprehensive structural view of affinity maturation. Correlating crystallographically observed structural changes with measured energetic changes reveals molecular bases for affinity maturation, intramolecular cooperativity, and context-dependent binding.