Structural basis of affinity maturation and intramolecular cooperativity in a protein-protein interaction.

Printer-friendly versionPrinter-friendly versionPDF versionPDF version
TitleStructural basis of affinity maturation and intramolecular cooperativity in a protein-protein interaction.
Publication TypeJournal Article
Year of Publication2005
AuthorsCho, S, Swaminathan, CP, Yang, J, Kerzic, MC, Guan, R, Kieke, MC, Kranz, DM, Mariuzza, RA, Sundberg, EJ
JournalStructure
Volume13
Issue12
Pagination1775-87
Date Published2005 Dec
ISSN0969-2126
KeywordsAmino Acid Substitution, Animals, Crystallography, X-Ray, Enterotoxins, Mice, Models, Molecular, Mutation, Peptide Fragments, Protein Conformation, Protein Interaction Mapping, Receptors, Antigen, T-Cell, alpha-beta, Water
Abstract

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.

DOI10.1016/j.str.2005.08.015
Alternate JournalStructure
PubMed ID16338406
PubMed Central IDPMC2746401
Grant ListAI064611 / AI / NIAID NIH HHS / United States
AI49564 / AI / NIAID NIH HHS / United States
AI55882 / AI / NIAID NIH HHS / United States
GM52801 / GM / NIGMS NIH HHS / United States
GM55767 / GM / NIGMS NIH HHS / United States
R37 AI036900-12 / AI / NIAID NIH HHS / United States