2FX7

Crystal structure of hiv-1 neutralizing human fab 4e10 in complex with a 16-residue peptide encompassing the 4e10 epitope on gp41

Summary for 2FX7

• Entry DOI: 10.2210/pdb2fx7/pdb
• Related: 1TZG 2FX8 2FX9
• Descriptor: Fab 4E10, Fragment of HIV glycoprotein (GP41), GLYCEROL, ... (5 entities in total)
• Functional Keywords: immunoglobulin fold, beta-sandwich, antibody-epitope complex, immune system
• Biological source: Homo sapiens (human); More
• Cellular location: Transmembrane protein gp41: Virion membrane; Single-pass type I membrane protein. Surface protein gp120: Virion membrane; Peripheral membrane protein: P05880
• Total number of polymer chains: 3
• Total formula weight: 49562.41

Authors

Cardoso, R.M.F.,Brunel, F.M.,Ferguson, S.,Burton, D.R.,Dawson, P.E.,Wilson, I.A. (deposition date: 2006-02-03, release date: 2006-12-19, Last modification date: 2023-08-30)

Primary citation

Cardoso, R.M.,Brunel, F.M.,Ferguson, S.,Zwick, M.,Burton, D.R.,Dawson, P.E.,Wilson, I.A.
Structural basis of enhanced binding of extended and helically constrained peptide epitopes of the broadly neutralizing HIV-1 antibody 4E10.
J.Mol.Biol., 365:1533-1544, 2007

PubMed 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.

PubMed: 17125793
DOI: 10.1016/j.jmb.2006.10.088

Experimental method

X-RAY DIFFRACTION (1.76 Å)