9C9M

HIV-1 intasome core bound with DTG

Summary for 9C9M

• Entry DOI: 10.2210/pdb9c9m/pdb
• EMDB information: 45364
• Descriptor: Integrase, viral DNA, vDNA, ... (8 entities in total)
• Functional Keywords: hiv-1, integrase, nucleoprotein complexes, insti, intasome, cryoem, viral protein
• Biological source: Human immunodeficiency virus 1; More
• Total number of polymer chains: 12
• Total formula weight: 296380.97

Authors

Li, M.,Craigie, R. (deposition date: 2024-06-14, release date: 2024-07-31, Last modification date: 2025-05-21)

Primary citation

Li, M.,Li, Z.,Chen, X.,Cui, Y.,Engelman, A.N.,Craigie, R.
HIV-1 Intasomes Assembled with Excess Integrase C-Terminal Domain Protein Facilitate Structural Studies by Cryo-EM and Reveal the Role of the Integrase C-Terminal Tail in HIV-1 Integration.
Viruses, 16:-, 2024

PubMed Abstract: Retroviral integration is mediated by intasome nucleoprotein complexes wherein a pair of viral DNA ends are bridged together by a multimer of integrase (IN). Atomic-resolution structures of HIV-1 intasomes provide detailed insights into the mechanism of integration and inhibition by clinical IN inhibitors. However, previously described HIV-1 intasomes are highly heterogeneous and have the tendency to form stacks, which is a limiting factor in determining high-resolution cryo-EM maps. We have assembled HIV-1 intasomes in the presence of excess IN C-terminal domain protein, which was readily incorporated into the intasomes. The purified intasomes were largely homogeneous and exhibited minimal stacking tendencies. The cryo-EM map resolution was further improved to 2.01 Å, which will greatly facilitate structural studies of IN inhibitor action and drug resistance mechanisms. The C-terminal 18 residues of HIV-1 IN, which are critical for virus replication and integration in vitro, have not been well resolved in previous intasome structures, and its function remains unclear. We show that the C-terminal tail participates in intasome assembly, resides within the intasome core, and forms a small alpha helix (residues 271-276). Mutations that disrupt alpha helix integrity impede IN activity in vitro and disrupt HIV-1 infection at the step of viral DNA integration.

PubMed: 39066328
DOI: 10.3390/v16071166

Experimental method

ELECTRON MICROSCOPY (2.01 Å)