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

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 determine...

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Bibliographic Details
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
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Summary: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.
ISSN:0969-2126
1878-4186
DOI:10.1016/j.str.2005.08.015