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

Sangwoo Cho, Chittoor P. Swaminathan, Jianying Yang, Melissa C. Kerzic, Rongjin Guan, Michele C. Kieke, David M. Kranz, Roy A. Mariuzza, Eric J. Sundberg

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1775-1787
Number of pages13
Issue number12
StatePublished - Dec 2005
Externally publishedYes

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology


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