RT Journal Article
SR Electronic
T1 MicroED Structures of HIV-1 Gag CTD-SP1 Reveal Binding Interactions with the Maturation Inhibitor Bevirimat
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 241182
DO 10.1101/241182
A1 Purdy, Michael D.
A1 Shi, Dan
A1 Chrustowicz, Jakub
A1 Hattne, Johan
A1 Gonen, Tamir
A1 Yeager, Mark
YR 2017
UL http://biorxiv.org/content/early/2017/12/30/241182.abstract
AB HIV-1 protease (PR) cleavage of the Gag polyprotein triggers the assembly of mature, infectious particles. Final cleavage of Gag occurs at the junction helix between the capsid protein CA and the SP1 spacer peptide. Here we used MicroED to delineate the binding interactions of the maturation inhibitor bevirimat (BVM) using very thin frozen-hydrated, three-dimensional microcrystals of a CTD-SP1 Gag construct with and without bound BVM. The 2.9-Å MicroED structure revealed that a single BVM molecule stabilizes the 6-helix bundle via both electrostatic interactions with the dimethysuccinyl moiety and hydrophobic interactions with the pentacyclic triterpenoid ring. These results provide insight into the mechanism of action of BVM and related maturation inhibitors that will inform further drug discovery efforts. This study also demonstrates the capabilities of MicroED for structure-based drug design.One-sentence summary The MicroED structure of HIV-1 Gag CTD-SP1 at 2.9 Å resolution reveals the molecular basis for binding of the maturation inhibitor bevirimat that will inform further drug discovery efforts.