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Structural basis for HIV‐1 DNA integration in the human genome, role of the LEDGF/P75 cofactor
Author(s) -
Michel Fabrice,
Crucifix Corinne,
Granger Florence,
Eiler Sylvia,
Mouscadet JeanFrançois,
Korolev Sergei,
Agapkina Julia,
Ziganshin Rustam,
Gottikh Marina,
Nazabal Alexis,
Emiliani Stéphane,
Benarous Richard,
Moras Dino,
Schultz Patrick,
Ruff Marc
Publication year - 2009
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2009.41
Subject(s) - biology , cofactor , genome , dna , genetics , human immunodeficiency virus (hiv) , computational biology , microbiology and biotechnology , virology , enzyme , biochemistry , gene
Integration of the human immunodeficiency virus (HIV‐1) cDNA into the human genome is catalysed by integrase. Several studies have shown the importance of the interaction of cellular cofactors with integrase for viral integration and infectivity. In this study, we produced a stable and functional complex between the wild‐type full‐length integrase (IN) and the cellular cofactor LEDGF/p75 that shows enhanced in vitro integration activity compared with the integrase alone. Mass spectrometry analysis and the fitting of known atomic structures in cryo negatively stain electron microscopy (EM) maps revealed that the functional unit comprises two asymmetric integrase dimers and two LEDGF/p75 molecules. In the presence of DNA, EM revealed the DNA‐binding sites and indicated that, in each asymmetric dimer, one integrase molecule performs the catalytic reaction, whereas the other one positions the viral DNA in the active site of the opposite dimer. The positions of the target and viral DNAs for the 3′ processing and integration reaction shed light on the integration mechanism, a process with wide implications for the understanding of viral‐induced pathologies.