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Zwick, MB; Komori, HK; Stanfield, RL; Church, S; Wang, M; Parren, PW; Kunert, R; Katinger, H; Wilson, IA; Burton, DR.
(2004): The long third complementarity-determining region of the heavy chain is important in the activity of the broadly neutralizing anti-human immunodeficiency virus type 1 antibody 2F5.
J Virol. 2004; 78(6):3155-3161 FullText FullText_BOKU

Abstract:
The human monoclonal antibody 2F5 neutralizes primary human immunodeficiency virus type 1 (HfV-1) with rare breadth and potency. A crystal structure of a complex of 2F5 and a peptide corresponding to its core epitope on gp41, ELDKWAS, revealed that the peptide interacts with residues at the base of the unusually long (22-residue) third complementarity-determining region of the heavy chain (CDR H3) but not the apex. Here, we perform alanine-scanning mutagenesis across CDR H3 and make additional substitutions of selected residues to map the paratope of Fab 2F5. Substitution of residues from the base of the H3 loop or from CDRs H1, H2, and L3, which are proximal to the peptide, significantly diminished the affinity of Fab 2F5 for gp41 and a short peptide containing the 2F5 core motif. However, nonconservative substitutions to a phenylalanine residue at the apex of the H3 loop also markedly decreased 2F5 binding to both gp41 and the peptide, suggesting that recognition of the core epitope is crucially dependent on features at the apex of the H3 loop. Furthermore, substitution at the apex of the H3 loop had an even more pronounced effect on the neutralizing activity of 2F5 against three sensitive HIV-1. These observations present a challenge to vaccine strategies based on peptide mimics of the linear epitope.
Authors BOKU Wien:
Katinger Hermann
Kunert Renate
Find related publications in this database (using NML MeSH Indexing)
Amino Acid Sequence -
Antibodies, Monoclonal - chemistry
Complementarity Determining Regions - chemistry
Epitopes - chemistry
HIV Antibodies - chemistry
HIV Envelope Protein gp41 - immunology
Humans - immunology
Models, Molecular - immunology
Molecular Sequence Data - immunology
Mutagenesis - immunology
Neutralization Tests - immunology



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