MicroED structures of HIV-1 Gag CTD-SP1 reveal binding interactions with the maturation inhibitor bevirimat.
Michael D PurdyDan ShiJakub ChrustowiczJohan HattneTamir GonenMark YeagerPublished in: Proceedings of the National Academy of Sciences of the United States of America (2018)
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, 3D 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 six-helix bundle via both electrostatic interactions with the dimethylsuccinyl 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.
Keyphrases
- dna binding
- drug discovery
- antiretroviral therapy
- hiv positive
- hiv infected
- hiv testing
- human immunodeficiency virus
- transcription factor
- hepatitis c virus
- hiv aids
- men who have sex with men
- single cell
- binding protein
- ionic liquid
- high resolution
- gene expression
- genome wide
- south africa
- dna methylation
- quality improvement
- protein protein
- molecular dynamics simulations
- amino acid
- small molecule
- aqueous solution