1. Structural basis for diverse N-glycan recognition by HIV-1-neutralizing V1-V2-directed antibody PG16.
- Author
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Pancera M, Shahzad-Ul-Hussan S, Doria-Rose NA, McLellan JS, Bailer RT, Dai K, Loesgen S, Louder MK, Staupe RP, Yang Y, Zhang B, Parks R, Eudailey J, Lloyd KE, Blinn J, Alam SM, Haynes BF, Amin MN, Wang LX, Burton DR, Koff WC, Nabel GJ, Mascola JR, Bewley CA, and Kwong PD
- Subjects
- Amino Acid Motifs, Amino Acid Sequence, Antibodies, Neutralizing chemistry, Antibodies, Neutralizing metabolism, Antibody Specificity, Antigen-Antibody Reactions, Binding Sites, Antibody, Carbohydrate Conformation, Carbohydrate Sequence, Crystallography, X-Ray, Epitopes chemistry, Epitopes immunology, Epitopes metabolism, Glycosylation drug effects, HEK293 Cells, HIV Antibodies chemistry, HIV Antibodies metabolism, HIV Envelope Protein gp120 chemistry, HIV Envelope Protein gp120 metabolism, Humans, Immunoglobulin Fab Fragments immunology, Immunoglobulin Fab Fragments metabolism, Models, Molecular, Molecular Sequence Data, Peptide Fragments chemistry, Peptide Fragments metabolism, Polysaccharides chemistry, Polysaccharides metabolism, Protein Conformation, Protein Processing, Post-Translational drug effects, Structure-Activity Relationship, Swainsonine pharmacology, Antibodies, Neutralizing immunology, HIV Antibodies immunology, HIV Envelope Protein gp120 immunology, Peptide Fragments immunology, Polysaccharides immunology
- Abstract
HIV-1 uses a diverse N-linked-glycan shield to evade recognition by antibody. Select human antibodies, such as the clonally related PG9 and PG16, recognize glycopeptide epitopes in the HIV-1 V1-V2 region and penetrate this shield, but their ability to accommodate diverse glycans is unclear. Here we report the structure of antibody PG16 bound to a scaffolded V1-V2, showing an epitope comprising both high mannose-type and complex-type N-linked glycans. We combined structure, NMR and mutagenesis analyses to characterize glycan recognition by PG9 and PG16. Three PG16-specific residues, arginine, serine and histidine (RSH), were critical for binding sialic acid on complex-type glycans, and introduction of these residues into PG9 produced a chimeric antibody with enhanced HIV-1 neutralization. Although HIV-1-glycan diversity facilitates evasion, antibody somatic diversity can overcome this and can provide clues to guide the design of modified antibodies with enhanced neutralization.
- Published
- 2013
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