title: Supersite of immune vulnerability on the glycosylated face of HIV-1 envelope glycoprotein gp120.
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.
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Leopold
authors.initials: L
authors.lastname: Kong
authors.forename: Jeong Hyun
authors.initials: JH
authors.lastname: Lee
authors.forename: Katie J
authors.initials: KJ
authors.lastname: Doores
authors.forename: Charles D
authors.initials: CD
authors.lastname: Murin
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Julien
authors.forename: Ryan
authors.initials: R
authors.lastname: McBride
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Andre
authors.initials: A
authors.lastname: Marozsan
authors.forename: Albert
authors.initials: A
authors.lastname: Cupo
authors.forename: Per-Johan
authors.initials: PJ
authors.lastname: Klasse
authors.forename: Simon
authors.initials: S
authors.lastname: Hoffenberg
authors.forename: Michael
authors.initials: M
authors.lastname: Caulfield
authors.forename: C Richter
authors.initials: CR
authors.lastname: King
authors.forename: Yuanzi
authors.initials: Y
authors.lastname: Hua
authors.forename: Khoa M
authors.initials: KM
authors.lastname: Le
authors.forename: Reza
authors.initials: R
authors.lastname: Khayat
authors.forename: Marc C
authors.initials: MC
authors.lastname: Deller
authors.forename: Thomas
authors.initials: T
authors.lastname: Clayton
authors.forename: Henry
authors.initials: H
authors.lastname: Tien
authors.forename: Ten
authors.initials: T
authors.lastname: Feizi
authors.forename: Rogier W
authors.initials: RW
authors.lastname: Sanders
authors.forename: James C
authors.initials: JC
authors.lastname: Paulson
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
authors.forename: Robyn L
authors.initials: RL
authors.lastname: Stanfield
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Burton
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Ward
authors.forename: Ian A
authors.initials: IA
authors.lastname: Wilson
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives / Q000494:pharmacology; D000470:Alkaloids / Q000494:pharmacology; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D057134:Antibodies, Neutralizing / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D000937:Antigen-Antibody Reactions; D001666:Binding Sites, Antibody; D001704:Biopolymers; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism; D002240:Carbohydrate Sequence; D018360:Crystallography, X-Ray; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D006031:Glycosylation / Q000187:drug effects; D057809:HEK293 Cells; D015483:HIV Antibodies / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology / Q000378:metabolism; D008854:Microscopy, Electron; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D011134:Polysaccharides / Q000502:physiology; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D013329:Structure-Activity Relationship; D054299:env Gene Products, Human Immunodeficiency Virus / Q000276:immunology
chemical_list: D000470:Alkaloids; D057134:Antibodies, Neutralizing; D001704:Biopolymers; D015704:CD4 Antigens; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D007140:Immunoglobulin Fab Fragments; D011134:Polysaccharides; D054299:env Gene Products, Human Immunodeficiency Virus; C514793:gp120 protein, Human immunodeficiency virus 1; C097729:gp140 envelope protein, Human immunodeficiency virus 1; C065629:kifunensine; D017485:1-Deoxynojirimycin; C059896:miglustat