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

• Published in: Structure (London) 2005-12, Vol.13 (12), p.1775-1787
• Main Authors: Cho, Sangwoo, Swaminathan, Chittoor P., Yang, Jianying, Kerzic, Melissa C., Guan, Rongjin, Kieke, Michele C., Kranz, David M., Mariuzza, Roy A., Sundberg, Eric J.
• Format: Article
• Language: English
• Subjects: Amino Acid Substitution; Animals; Crystallography, X-Ray; Enterotoxins - chemistry; Enterotoxins - genetics; Mice; Models, Molecular; Mutation; Peptide Fragments - chemistry; Peptide Fragments - genetics; Protein Conformation; Protein Interaction Mapping; Receptors, Antigen, T-Cell, alpha-beta - chemistry; Receptors, Antigen, T-Cell, alpha-beta - genetics; Water - chemistry
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2005.08.015

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.