Epitopes described in "Structural basis of enhanced binding of extended and helically constrained peptide epitopes of the broadly neutralizing HIV-1 antibody 4E10."

Reference
Article Authors:Rosa M F Cardoso; Florence M Brunel; Sharon Ferguson; Michael Zwick; Dennis R Burton; Philip E Dawson; Ian A Wilson
Article Title:Structural basis of enhanced binding of extended and helically constrained peptide epitopes of the broadly neutralizing HIV-1 antibody 4E10.
Reference Detail
Reference ID:1022127
Abstract:Potent, broadly HIV-1 neutralizing antibodies (nAbs) may be invaluable for the design of an AIDS vaccine. 4E10 is the broadest HIV-1 nAb known to date and recognizes a contiguous and highly conserved helical epitope in the membrane-proximal region of gp41. The 4E10 epitope is thus an excellent target for vaccine design as it is also highly amenable to peptide engineering to enhance its helical character. To investigate the structural effect of both increasing the peptide length and of introducing helix-promoting constraints in the 4E10 epitope, we have determined crystal structures of Fab 4E10 bound to an optimized peptide epitope (NWFDITNWLWYIKKKK-NH(2)), an Aib-constrained peptide epitope (NWFDITNAibLWRR-NH(2)), and a thioether-linked peptide (NWFCITOWLWKKKK-NH(2)) to resolutions of 1.7 A, 2.1 A, and 2.2 A, respectively. The thioether-linked peptide is the first reported structure of a cyclic tethered helical peptide bound to an antibody. The introduced helix constraints limit the conformational flexibility of the peptides without affecting interactions with 4E10. The substantial increase in affinity (10 nM versus 10(4) nM of the IC(50) of the original KGND peptide template) is largely realized by 4E10 interaction with an additional helical turn at the peptide C terminus that includes Leu679 and Trp680. Thus, the core 4E10 epitope was extended and modified to a WFX(I/L)(T/S)XX(L/I)W motif, where X does not play a major role in 4E10 binding and can be used to introduce helical-promoting constraints in the peptide epitope.
Affiliations:Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Date:2007
Reference Type:Literature
PubMed ID:17125793
Journal:J Mol Biol
Journal Volume:365
Article Pages:1533-44
Journal ISSN:1089-8638
Article Chemical List:Epitopes;HIV Antibodies;Immunoglobulin Fab Fragments;Peptides
Article MeSH List:Amino Acid Sequence; Antibody Affinity(immunology); Binding Sites, Antibody(immunology); Epitopes(chemistry); HIV Antibodies(immunology); HIV-1(immunology); Hydrogen Bonding; Immunoglobulin Fab Fragments(immunology); Models, Molecular; Molecular Sequence Data; Peptides(chemistry); Protein Binding; Protein Structure, Secondary; Structural Homology, Protein; Structure-Activity Relationship; X-Ray Diffraction
Curation Last Updated:2014-10-03 22:21:00