Crystal structure of a neutralizing human IGG against HIV-1: a template for vaccine design.
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.
Saphire
E O
EO
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.
Parren
P W
PW
Pantophlet
R
R
Zwick
M B
MB
Morris
G M
GM
Rudd
P M
PM
Dwek
R A
RA
Stanfield
R L
RL
Burton
D R
DR
Wilson
I A
IA
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
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