Structure of antibody F425-B4e8 in complex with a V3 peptide reveals a new binding mode for HIV-1 neutralization |
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Authors: | Bell Christian H Pantophlet Ralph Schiefner André Cavacini Lisa A Stanfield Robyn L Burton Dennis R Wilson Ian A |
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Institution: | 1 Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA 2 Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA 3 Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA 4 Harvard Medical School, Boston, MA 02115, USA 5 Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA |
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Abstract: | 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 Å resolution is described. The complex structure reveals that the antibody recognizes a novel V3 loop conformation, featuring a five-residue α-turn around the conserved GPGRA apex of the β-hairpin loop. In agreement with previous mutagenesis analyses, the Fab′ interacts primarily with V3 through side-chain contacts with just two residues, IleP309 and ArgP315, 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. |
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Keywords: | HIV-1 human immunodeficiency virus type 1 mAb monoclonal antibody SIV simian immunodeficiency virus |
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