title: Broadly neutralizing anti-HIV antibody 4E10 recognizes a helical conformation of a highly conserved fusion-associated motif in gp41.
abstract: Broadly neutralizing monoclonal antibodies to HIV-1 are rare but invaluable for vaccine design. 4E10 is the broadest neutralizing antibody known and recognizes a contiguous and highly conserved epitope in the membrane-proximal region of gp41. The crystal structure of Fab 4E10 was determined at 2.2 A resolution in complex with a 13-residue peptide containing the gp41 core epitope (NWFDIT). The bound peptide adopts a helical conformation in which the key contact residues, TrpP672, PheP673, IleP675, and ThrP676, map to one face of the helix. The peptide binds in a hydrophobic pocket that may emulate its potential interaction with the host cell membrane. The long CDR H3 of the antibody extends beyond the bound peptide in an orientation that suggests that its apex could contact the viral membrane when 4E10 is bound to its membrane-proximal epitope. These structural insights should assist in the design of immunogens to elicit 4E10-like neutralizing responses.
authors.affiliation: Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Rosa M F
authors.initials: RM
authors.lastname: Cardoso
authors.forename: Michael B
authors.initials: MB
authors.lastname: Zwick
authors.forename: Robyn L
authors.initials: RL
authors.lastname: Stanfield
authors.forename: Renate
authors.initials: R
authors.lastname: Kunert
authors.forename: James M
authors.initials: JM
authors.lastname: Binley
authors.forename: Hermann
authors.initials: H
authors.lastname: Katinger
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Burton
authors.forename: Ian A
authors.initials: IA
authors.lastname: Wilson
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D000918:Antibody Specificity; D001666:Binding Sites, Antibody; D002460:Cell Line; D017124:Conserved Sequence; D006224:Cricetinae; D018360:Crystallography, X-Ray; D018985:Epitopes, B-Lymphocyte / Q000276:immunology; D015483:HIV Antibodies / Q000737:chemistry / Q000276:immunology*; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D006860:Hydrogen Bonding; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000276:immunology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D011487:Protein Conformation; D055672:Static Electricity
chemical_list: D018985:Epitopes, B-Lymphocyte; D015483:HIV Antibodies; D015700:HIV Envelope Protein gp41; D007140:Immunoglobulin Fab Fragments