P15.28 LB
Background: The HIV-1-envelope (Env) spike is a conformational machine that switches between prefusion and postfusion conformations to facilitate HIV-1 entry. Extensive interest has focused on the prefusion mature closed conformation, as it is the target of neutralizing antibodies. One hall-mark of this conformation is the recognition by the small molecule entry inhibitor, BMS-806, which is currently in pre-clinical trial. Mutagenesis has shown that BMS-806 binds to specific residues within the CD4-binding pocket of Env. The mechanism of BMS-806 remains unclear.
Methods: We obtained a lattice of HIV-1 Env, bound by antibodies 35O22 and PGT122 that diffracts sufficiently to allow chemical details to be visualized by X-ray crystallography. By using this lattice, we were able to visualize how BMS-806 binds to HIV-1 Env in the context of a prefusion closed mature state using BG505 SOSIP.664.
Results: Structure of BMS-806 bound to BG505 SOSIP.664 will be presented and comparison to unbound structure will reveal BMS-806 mechanism.
Conclusions: We obtained a structure of BMS-806, a potent entry inhibitor, bound to HIV-1 Env trimer. Binding of BMS-806 to the 35O22/PGT122-bound trimer provides additional evidence for the functional validity of this antibody-bound structure. Moreover, the chemical details of BMS-806 interaction should allow for its structure-based enhancement.