Structure of Antibody F425-B4e8 in Complex With a V3 Peptide Reveals a New Binding Mode for Hiv-1 Neutralization

Journal Article · Mon May 11 04:00:00 EDT 2009 · J. Mol. Biol. 375:969,2008

OSTI ID:958632

Bell, C H; Pantophlet, R; Schiefner, A; Cavacini, L A; Stanfield, R L; Burton, D R; Wilson, I A

F425-B4e8 (B4e8) is a monoclonal antibody isolated from a human immunodeficiency virus type 1 (HIV-1)-infected individual that recognizes the V3 variable loop on the gp120 subunit of the viral envelope spike. B4e8 neutralizes a subset of HIV-1 primary isolates from subtypes B, C and D, which places this antibody among the very few human anti-V3 antibodies with notable cross-neutralizing activity. Here, the crystal structure of the B4e8 Fab fragment in complex with a 24-mer V3 peptide (RP142) at 2.8 A resolution is described. The complex structure reveals that the antibody recognizes a novel V3 loop conformation, featuring a five-residue alpha-turn around the conserved GPGRA apex of the beta-hairpin loop. In agreement with previous mutagenesis analyses, the Fab interacts primarily with V3 through side-chain contacts with just two residues, Ile(P309) and Arg(P315), while the remaining contacts are to the main chain. The structure helps explain how B4e8 can tolerate a certain degree of sequence variation within V3 and, hence, is able to neutralize an appreciable number of different HIV-1 isolates.

• Research Organization: Stanford Linear Accelerator Center (SLAC)
• Sponsoring Organization: USDOE
• DOE Contract Number: AC02-76SF00515
• OSTI ID: 958632
• Report Number(s): SLAC-REPRINT-2009-057
• Journal Information: J. Mol. Biol. 375:969,2008, Journal Name: J. Mol. Biol. 375:969,2008 Journal Issue: 4 Vol. 375; ISSN JMOBAK; ISSN 0022-2836
• Country of Publication: United States
• Language: English

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