A supramolecular assembly mediates lentiviral DNA integration

Science. 2017 Jan 6;355(6320):93-95. doi: 10.1126/science.aah7002.

Abstract

Retroviral integrase (IN) functions within the intasome nucleoprotein complex to catalyze insertion of viral DNA into cellular chromatin. Using cryo-electron microscopy, we now visualize the functional maedi-visna lentivirus intasome at 4.9 angstrom resolution. The intasome comprises a homo-hexadecamer of IN with a tetramer-of-tetramers architecture featuring eight structurally distinct types of IN protomers supporting two catalytically competent subunits. The conserved intasomal core, previously observed in simpler retroviral systems, is formed between two IN tetramers, with a pair of C-terminal domains from flanking tetramers completing the synaptic interface. Our results explain how HIV-1 IN, which self-associates into higher-order multimers, can form a functional intasome, reconcile the bulk of early HIV-1 IN biochemical and structural data, and provide a lentiviral platform for design of HIV-1 IN inhibitors.

Publication types

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

MeSH terms

  • Catalytic Domain
  • Cryoelectron Microscopy
  • DNA, Viral / chemistry
  • DNA, Viral / ultrastructure
  • Drug Design
  • HIV Integrase / chemistry*
  • HIV Integrase / ultrastructure
  • HIV Integrase Inhibitors / chemistry
  • HIV-1 / chemistry*
  • HIV-1 / enzymology
  • HIV-1 / ultrastructure
  • Humans
  • Models, Molecular
  • Protein Domains
  • Static Electricity
  • Virus Assembly
  • Virus Integration*

Substances

  • DNA, Viral
  • HIV Integrase Inhibitors
  • HIV Integrase
  • p31 integrase protein, Human immunodeficiency virus 1