Broadly Neutralizing Antibody PGT121 Allosterically Modulates CD4 Binding via Recognition of the HIV-1 gp120 V3 Base and Multiple Surrounding Glycans
Figure 5
Model of HIV Env recognition by antibodies of the PGT121 family.
A model of the PGT 121 family interaction with Env trimer is shown on the bottom right and was generated from the electron microscopy reconstruction of the unliganded membrane-anchored HIV-1 Env trimer (gray surface, EMDB ID 5019 and 5021 [35]) with modeled glycans and PGT121 Fab as blue spheres and green surface, respectively. The large inset is a close-up view of the fitting of the PGT121 Fab crystal structure (light and heavy chains are colored in light and dark green, respectively) and the eODmV3 crystal structure (colored in gray), as bound by the PGT128 Fab (PDB ID 3TYG [29]) in the negative-stain EM reconstruction (transparent gray mesh). The crystal structures of the PGT121 Fab and the gp120 outer domain are rendered as secondary structure cartoons. PGT121 paratope residues identified as most important for mediating HIV-1 neutralization are shown as red and orange spheres according to the scheme used in Fig. 2. In this model, crucial residues of the PGT121 paratope in the elongated face (rendered as red spheres) are located near the base of the gp120 V3 loop (black). Consistent with the biochemical data, the antibody paratope is located near the N332 glycan (rendered as yellow sticks and surface). Glycosylation at this position is crucial for recognition by antibodies of the PGT121 family. In addition, the PGT121 paratope is located in close proximity to the N301 glycan (rendered as cyan sticks and surface), as well as putative complex glycan (rendered as magenta sticks and surface) observed in the PGT121 crystal structure of unknown location on gp120 but close to V1/V2 in the model. For this complex glycan, the two N-acetylglucosamines (NAG) that would be attached to the Asn on the protein point in the direction of the region associated with gp120 V1/V2 loops. Together, our data show that PGT 121 binding to this epitope appears to allosterically block CD4 engagement. The CD4 binding site is colored blue. The figure was generated using UCSF Chimera [70].