Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 102, Issue 48, Pages 17308-17313Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0506924102
Keywords
integration; structure; retrovirus; transcription; host factor
Categories
Funding
- NIAID NIH HHS [R21 AI062249, R37 AI039394, AI62249, R01 AI039394, AI39394] Funding Source: Medline
- NIGMS NIH HHS [GM59902, R01 GM059902] Funding Source: Medline
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Integrase (IN) is an essential retroviral enzyme, and human transcriptional coactivator p75, which is also referred to as lens epithelium-derived growth factor (LEDGF), is the dominant cellular binding partner of HIV-1 IN. Here, we report the crystal structure of the dimeric catalytic core domain of HIV-1 IN complexed to the IN-binding domain of LEDGF. Previously identified LEDGF hotspot residues anchor the protein to both monomers at the IN dinner interface. The principal structural features of IN that are recognized by the host factor are the backbone conformation of residues 168-171 from one monomer and a hydrophobic patch that is primarily comprised of a-helices 1 and 3 of the second IN monomer. inspection of diverse retroviral primary and secondary sequence elements helps to explain the apparent lentiviral tropism of the LEDGF-IN interaction. Because the lethal phenotypes of HIV-1 mutant viruses unable to interact with LEDGF indicate that IN function is highly sensitive to perturbations of the structure around the LEDGF-binding site, we propose that small molecule inhibitors of the protein-protein interaction might similarly disrupt HIV-1 replication.
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