5T33

Crystal structure of strain-specific glycan-dependent CD4 binding site-directed neutralizing antibody CAP257-RH1, in complex with HIV-1 strain RHPA gp120 core with an oligomannose N276 glycan.

Summary for 5T33

• Entry DOI: 10.2210/pdb5t33/pdb
• Descriptor: CAP257-RH1 heavy chain, CAP257-RH1 light chain, RHPA gp120 core, ... (7 entities in total)
• Functional Keywords: hiv, strain-specific, neutralizing antibody, cd4 binding site, n276 glycan, glycan-free v5, immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 3
• Total formula weight: 91003.32

Authors

Wibmer, C.K.,Gorman, J.,Kwong, P.D. (deposition date: 2016-08-24, release date: 2016-09-07, Last modification date: 2024-10-30)

Primary citation

Wibmer, C.K.,Gorman, J.,Anthony, C.S.,Mkhize, N.N.,Druz, A.,York, T.,Schmidt, S.D.,Labuschagne, P.,Louder, M.K.,Bailer, R.T.,Abdool Karim, S.S.,Mascola, J.R.,Williamson, C.,Moore, P.L.,Kwong, P.D.,Morris, L.
Structure of an N276-Dependent HIV-1 Neutralizing Antibody Targeting a Rare V5 Glycan Hole Adjacent to the CD4 Binding Site.
J.Virol., 90:10220-10235, 2016

PubMed Abstract: All HIV-1-infected individuals develop strain-specific neutralizing antibodies to their infecting virus, which in some cases mature into broadly neutralizing antibodies. Defining the epitopes of strain-specific antibodies that overlap conserved sites of vulnerability might provide mechanistic insights into how broadly neutralizing antibodies arise. We previously described an HIV-1 clade C-infected donor, CAP257, who developed broadly neutralizing plasma antibodies targeting an N276 glycan-dependent epitope in the CD4 binding site. The initial CD4 binding site response potently neutralized the heterologous tier 2 clade B viral strain RHPA, which was used to design resurfaced gp120 antigens for single-B-cell sorting. Here we report the isolation and structural characterization of CAP257-RH1, an N276 glycan-dependent CD4 binding site antibody representative of the early CD4 binding site plasma response in donor CAP257. The cocrystal structure of CAP257-RH1 bound to RHPA gp120 revealed critical interactions with the N276 glycan, loop D, and V5, but not with aspartic acid 368, similarly to HJ16 and 179NC75. The CAP257-RH1 monoclonal antibody was derived from the immunoglobulin-variable IGHV3-33 and IGLV3-10 genes and neutralized RHPA but not the transmitted/founder virus from donor CAP257. Its narrow neutralization breadth was attributed to a binding angle that was incompatible with glycosylated V5 loops present in almost all HIV-1 strains, including the CAP257 transmitted/founder virus. Deep sequencing of autologous CAP257 viruses, however, revealed minority variants early in infection that lacked V5 glycans. These glycan-free V5 loops are unusual holes in the glycan shield that may have been necessary for initiating this N276 glycan-dependent CD4 binding site B-cell lineage.

PubMed: 27581986
DOI: 10.1128/JVI.01357-16

Experimental method

X-RAY DIFFRACTION (3.2092 Å)