OA05.06 LB
Background: The first and second variable regions (V1V2) of gp120 play vital roles in the function of HIV-1 envelope (Env). V1V2, which harbors multiple glycans and is highly sequence diverse, is located at the Env apex and stabilizes the trimer. It shields V3 and the co-receptor binding site in the pre-fusion state and exposes them upon CD4 binding. Recent structural data, including that of the scaffolded V1V2 in complex with PG9/PG16 and the trimeric SOSIPs, suggested that V1V2 forms a Greek key motif with 4 beta strands (named strands A-D). However, regions of V1V2 including the integrin-binding site were missing from those structural visualizations, and our understanding of the V1V2 structure-function is thus not yet complete.
Methods: We have determined a crystal structure of the V1V2 scaffold (V1V2ZM109-1FD6) in complex with 830A, an anti-V1V2 human mAb with an epitope known to overlap the integrin-binding site.
Results: Our complex structure revealed that V1V2 has a 5-stranded beta barrel structure with the region of the integrin-binding site forming a kink (AAs 178–180) followed by an additional beta strand (strand C') before strand D. The complete barrel structure naturally presents the glycans on its outer surface and packs conserved hydrophobic residues, including the RV144 sieve residue Ile181, in its core,. The two length-varying regions in V1 and V2 form two extended loops towards one end of the barrel. The epitope of 830A is discontinuous with three segments: it centers at Thr175, Tyr177, Leu179 and Asp180 at the kink overlapping the integrin-binding site (AAs 179–181) and also includes residues Arg153 and Val154 in V1 and Leu193, Ile194 and Ser195 at the C-terminus of V2.
Conclusions: The V1V2 region forms a 5-stranded beta barrel, a unique structure that can function as an independent module.
