Structural, energetic, and functional analysis of a protein-protein interface at distinct stages of affinity maturation.

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TitleStructural, energetic, and functional analysis of a protein-protein interface at distinct stages of affinity maturation.
Publication TypeJournal Article
Year of Publication2003
AuthorsSundberg, EJ, Andersen, PS, Schlievert, PM, Karjalainen, K, Mariuzza, RA
JournalStructure
Volume11
Issue9
Pagination1151-61
Date Published2003 Sep
ISSN0969-2126
KeywordsBinding Sites, Enterotoxins, Histocompatibility Antigens Class II, HLA-DR1 Antigen, Hydrophobic and Hydrophilic Interactions, Lymphocyte Activation, Models, Molecular, Protein Binding, Protein Structure, Quaternary, Protein Structure, Tertiary, Signal Transduction, Superantigens, T-Lymphocytes
Abstract

Due to a paucity of studies that synthesize structural, energetic, and functional analyses of a series of protein complexes representing distinct stages in an affinity maturation pathway, the biophysical basis for the molecular evolution of protein-protein interactions is poorly understood. Here, we combine crystal structures and binding-free energies of a series of variant superantigen (SAG)-major histocompatibility complex (MHC) class II complexes exhibiting increasingly higher affinity to reveal that this affinity maturation pathway is controlled largely by two biophysical factors: shape complementarity and buried hydrophobic surface. These factors, however, do not contribute equivalently to the affinity maturation of the interface, as the former dominates the early steps of the maturation process while the latter is responsible for improved binding in later steps. Functional assays reveal how affinity maturation of the SAG-MHC interface corresponds to T cell activation by SAGs.

Alternate JournalStructure
PubMed ID12962633
Grant ListAI36900 / AI / NIAID NIH HHS / United States
AI49564 / AI / NIAID NIH HHS / United States