Structure and mechanistic analysis of the anti-human immunodeficiency virus type 1 antibody 2F5 in complex with its gp41 epitope.

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TitleStructure and mechanistic analysis of the anti-human immunodeficiency virus type 1 antibody 2F5 in complex with its gp41 epitope.
Publication TypeJournal Article
Year of Publication2004
AuthorsOfek, GA, Tang, M, Sambor, A, Katinger, H, Mascola, JR, Wyatt, R, Kwong, PD
JournalJ Virol
Volume78
Issue19
Pagination10724-37
Date Published2004 Oct
ISSN0022-538X
KeywordsAmino Acid Sequence, Complementarity Determining Regions, Crystallography, X-Ray, Epitopes, HIV Antibodies, HIV Envelope Protein gp41, HIV-1, Humans, Models, Molecular, Molecular Sequence Data, Neutralization Tests, Protein Binding, Protein Structure, Quaternary
Abstract

The membrane-proximal region of the ectodomain of the gp41 envelope glycoprotein of human immunodeficiency virus type 1 (HIV-1) is the target of three of the five broadly neutralizing anti-HIV-1 antibodies thus far isolated. We have determined crystal structures of the antigen-binding fragment for one of these antibodies, 2F5, in complex with 7-mer, 11-mer, and 17-mer peptides of the gp41 membrane-proximal region, at 2.0-, 2.1-, and 2.2-A resolutions, respectively. The structures reveal an extended gp41 conformation, which stretches over 30 A in length. Contacts are made with five complementarity-determining regions of the antibody as well as with nonpolymorphic regions. Only one exclusive charged face of the gp41 epitope is bound by 2F5, while the nonbound face, which is hydrophobic, may be hidden due to occlusion by other portions of the ectodomain. The structures reveal that the 2F5 antibody is uniquely built to bind to an epitope that is proximal to a membrane surface and in a manner mostly unaffected by large-scale steric hindrance. Biochemical studies with proteoliposomes confirm the importance of lipid membrane and hydrophobic context in the binding of 2F5 as well as in the binding of 4E10, another broadly neutralizing antibody that recognizes the membrane-proximal region of gp41. Based on these structural and biochemical results, immunization strategies for eliciting 2F5- and 4E10-like broadly neutralizing anti-HIV-1 antibodies are proposed.

DOI10.1128/JVI.78.19.10724-10737.2004
Alternate JournalJ. Virol.
PubMed ID15367639
PubMed Central IDPMC516390