2fx7
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Crystal structure of hiv-1 neutralizing human fab 4e10 in complex with a 16-residue peptide encompassing the 4e10 epitope on gp41
OverviewOverview
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.
About this StructureAbout this Structure
2FX7 is a Single protein structure of sequence from Homo sapiens with GOL as ligand. Full crystallographic information is available from OCA.
ReferenceReference
Structural basis of enhanced binding of extended and helically constrained peptide epitopes of the broadly neutralizing HIV-1 antibody 4E10., Cardoso RM, Brunel FM, Ferguson S, Zwick M, Burton DR, Dawson PE, Wilson IA, J Mol Biol. 2007 Feb 2;365(5):1533-44. Epub 2006 Nov 10. PMID:17125793
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