Evolutionary transition pathways for changing peptide ligand specificity and structure

We identified evolutionary pathways for the inter‐ conversion of three sequentially and structurally unrelated peptides, GATPEDLNQKL, GLYEWGGARI and FDKEWNLIEQN, binding to the same site of the hypervariable region of the anti‐p24 (HIV‐1) monoclonal antibody CB4‐1. Conversion of these peptides into...

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Bibliographic Details
Published in:The EMBO journal 2000-09, Vol.19 (18), p.4866-4874
Main Authors: Hoffmüller, Ulrich, Knaute, Tobias, Hahn, Michael, Höhne, Wolfgang, Schneider-Mergener, Jens, Kramer, Achim
Format: Article
Language:English
Subjects:
Algorithms
Amino Acid Sequence
Amino acids
Amino Acids - chemistry
Antibodies, Monoclonal - chemistry
Biosensing Techniques
Cellulose - chemistry
Crystallography, X-Ray
Enzyme-Linked Immunosorbent Assay
Evolution, Molecular
HIV Core Protein p24 - chemistry
Ligands
Magnetic Resonance Spectroscopy
Models, Molecular
molecular evolution
Molecular Sequence Data
Peptide Biosynthesis
peptide library
Peptides
Peptides - chemistry
Phenotype
Protein Binding
Protein Conformation
spot synthesis
Structure-Activity Relationship
transition pathways
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Summary:We identified evolutionary pathways for the inter‐ conversion of three sequentially and structurally unrelated peptides, GATPEDLNQKL, GLYEWGGARI and FDKEWNLIEQN, binding to the same site of the hypervariable region of the anti‐p24 (HIV‐1) monoclonal antibody CB4‐1. Conversion of these peptides into each other could be achieved in nine or 10 single amino acid substitution steps without loss of antibody binding. Such pathways were identified by analyzing all 7 620 480 pathways connecting 2560 different peptides, and testing them for CB4‐1 binding. The binding modes of intermediate peptides of selected optimal pathways were characterized using complete sets of substitution analogs, revealing that a number of sequential substitutions accumulated without changing the pattern of key interacting residues. At a distinct step, however, one single amino acid exchange induces a sudden change in the binding mode, indicating a flip in specificity and conformation. Our data represent a model of how different specificities, structures and functions might evolve in protein–protein recognition.
ISSN:0261-4189
1460-2075
1460-2075
DOI:10.1093/emboj/19.18.4866