1. MicroED structures of HIV-1 Gag CTD-SP1 reveal binding interactions with the maturation inhibitor bevirimat.
- Author
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Purdy MD, Shi D, Chrustowicz J, Hattne J, Gonen T, and Yeager M
- Subjects
- Anti-HIV Agents chemistry, Crystallography, X-Ray, Drug Resistance, Viral, Humans, Models, Molecular, Protein Domains, Succinates chemistry, Triterpenes chemistry, gag Gene Products, Human Immunodeficiency Virus antagonists & inhibitors, Anti-HIV Agents metabolism, Cryoelectron Microscopy methods, Protein Conformation, Succinates metabolism, Triterpenes metabolism, gag Gene Products, Human Immunodeficiency Virus chemistry, gag Gene Products, Human Immunodeficiency Virus metabolism
- Abstract
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., Competing Interests: The authors declare no conflict of interest.
- Published
- 2018
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