Supersite of Immune Vulnerability on the Glycosylated Face of HIV-1 Envelope Glycoprotein gp120

Nat Struct Mol Biol. 2013 Jul;20(7):796-803. doi: 10.1038/nsmb.2594. Epub 2013 May 26.

Abstract

A substantial proportion of the broadly neutralizing antibodies (bnAbs) identified in certain HIV-infected donors recognize glycan-dependent epitopes on HIV-1 gp120. Here we elucidate how the bnAb PGT 135 binds its Asn332 glycan-dependent epitope from its 3.1-Å crystal structure with gp120, CD4 and Fab 17b. PGT 135 interacts with glycans at Asn332, Asn392 and Asn386, using long CDR loops H1 and H3 to penetrate the glycan shield and access the gp120 protein surface. EM reveals that PGT 135 can accommodate the conformational and chemical diversity of gp120 glycans by altering its angle of engagement. Combined structural studies of PGT 135, PGT 128 and 2G12 show that this Asn332-dependent antigenic region is highly accessible and much more extensive than initially appreciated, which allows for multiple binding modes and varied angles of approach; thereby it represents a supersite of vulnerability for antibody neutralization.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Video-Audio Media

MeSH terms

  • 1-Deoxynojirimycin / analogs & derivatives
  • 1-Deoxynojirimycin / pharmacology
  • Alkaloids / pharmacology
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Antibodies, Neutralizing / chemistry
  • Antibodies, Neutralizing / immunology*
  • Antibodies, Neutralizing / metabolism
  • Antigen-Antibody Reactions
  • Binding Sites, Antibody
  • Biopolymers
  • CD4 Antigens / immunology
  • CD4 Antigens / metabolism
  • Carbohydrate Sequence
  • Crystallography, X-Ray
  • Epitopes / chemistry
  • Epitopes / immunology
  • Glycosylation / drug effects
  • HEK293 Cells
  • HIV Antibodies / chemistry
  • HIV Antibodies / immunology*
  • HIV Antibodies / metabolism
  • HIV Envelope Protein gp120 / chemistry
  • HIV Envelope Protein gp120 / immunology*
  • HIV Envelope Protein gp120 / metabolism
  • HIV Envelope Protein gp120 / ultrastructure
  • Humans
  • Immunoglobulin Fab Fragments / immunology
  • Immunoglobulin Fab Fragments / metabolism
  • Microscopy, Electron
  • Models, Molecular
  • Molecular Docking Simulation
  • Molecular Sequence Data
  • Polysaccharides / physiology
  • Protein Conformation
  • Protein Processing, Post-Translational / drug effects
  • Structure-Activity Relationship
  • env Gene Products, Human Immunodeficiency Virus / immunology

Substances

  • Alkaloids
  • Antibodies, Neutralizing
  • Biopolymers
  • CD4 Antigens
  • Epitopes
  • HIV Antibodies
  • HIV Envelope Protein gp120
  • Immunoglobulin Fab Fragments
  • Polysaccharides
  • env Gene Products, Human Immunodeficiency Virus
  • gp120 protein, Human immunodeficiency virus 1
  • gp140 envelope protein, Human immunodeficiency virus 1
  • kifunensine
  • 1-Deoxynojirimycin
  • miglustat

Associated data

  • PDB/4JM2
  • PDB/4JM4