MicroED structures of HIV-1 Gag CTD-SP1 reveal binding interactions with the maturation inhibitor bevirimat

Proc Natl Acad Sci U S A. 2018 Dec 26;115(52):13258-13263. doi: 10.1073/pnas.1806806115. Epub 2018 Dec 10.


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.

Keywords: Gag; HIV-1; cryoEM; drug discovery; maturation inhibitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / metabolism*
  • Cryoelectron Microscopy / methods*
  • Crystallography, X-Ray
  • Drug Resistance, Viral
  • Humans
  • Models, Molecular
  • Protein Conformation*
  • Protein Domains
  • Succinates / chemistry
  • Succinates / metabolism*
  • Triterpenes / chemistry
  • Triterpenes / metabolism*
  • gag Gene Products, Human Immunodeficiency Virus / antagonists & inhibitors
  • gag Gene Products, Human Immunodeficiency Virus / chemistry*
  • gag Gene Products, Human Immunodeficiency Virus / metabolism*


  • Anti-HIV Agents
  • Succinates
  • Triterpenes
  • gag Gene Products, Human Immunodeficiency Virus
  • bevirimat

Associated data

  • PDB/6N3J
  • PDB/6N3U