title: Crystal structure of a neutralizing human IGG against HIV-1: a template for vaccine design.
abstract: We present the crystal structure at 2.7 angstrom resolution of the human antibody IgG1 b12. Antibody b12 recognizes the CD4-binding site of human immunodeficiency virus-1 (HIV-1) gp120 and is one of only two known antibodies against gp120 capable of broad and potent neutralization of primary HIV-1 isolates. A key feature of the antibody-combining site is the protruding, finger-like long CDR H3 that can penetrate the recessed CD4-binding site of gp120. A docking model of b12 and gp120 reveals severe structural constraints that explain the extraordinary challenge in eliciting effective neutralizing antibodies similar to b12. The structure, together with mutagenesis studies, provides a rationale for the extensive cross-reactivity of b12 and a valuable framework for the design of HIV-1 vaccines capable of eliciting b12-like activity.
authors.affiliation: Department of Molecular Biology, Department of Immunology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: E O
authors.initials: EO
authors.lastname: Saphire
authors.forename: P W
authors.initials: PW
authors.lastname: Parren
authors.forename: R
authors.initials: R
authors.lastname: Pantophlet
authors.forename: M B
authors.initials: MB
authors.lastname: Zwick
authors.forename: G M
authors.initials: GM
authors.lastname: Morris
authors.forename: P M
authors.initials: PM
authors.lastname: Rudd
authors.forename: R A
authors.initials: RA
authors.lastname: Dwek
authors.forename: R L
authors.initials: RL
authors.lastname: Stanfield
authors.forename: D R
authors.initials: DR
authors.lastname: Burton
authors.forename: I A
authors.initials: IA
authors.lastname: Wilson
mesh_terms: D016915:AIDS Vaccines; D000595:Amino Acid Sequence; D001665:Binding Sites; D001666:Binding Sites, Antibody; D015704:CD4 Antigens / Q000378:metabolism; D022801:Complementarity Determining Regions / Q000737:chemistry; D018360:Crystallography, X-Ray; D000939:Epitopes; D015483:HIV Antibodies / Q000737:chemistry* / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D006860:Hydrogen Bonding; D007074:Immunoglobulin G / Q000737:chemistry* / Q000276:immunology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D019151:Peptide Library; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D013698:Templates, Genetic; D013816:Thermodynamics
chemical_list: D016915:AIDS Vaccines; D015704:CD4 Antigens; D022801:Complementarity Determining Regions; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D007074:Immunoglobulin G; D019151:Peptide Library