期刊
EMBO JOURNAL
卷 28, 期 7, 页码 980-991出版社
WILEY
DOI: 10.1038/emboj.2009.41
关键词
cryo-electron microscopy; DNA integration; HIV-1; integrase; LEDGF-P75
资金
- CNRS
- INSERM
- French National Agency for Research against AIDS (ANRS)
- RFBR (Russian Foundation for Basic Research) [08-04-01252, 0804-01293]
- the TrioH European Project [503480]
- SPINE 1 and 2 European Project [QLG2-CT-200200988, 031220]
- SIDACTION
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 30 processing and integration reaction shed light on the integration mechanism, a process with wide implications for the understanding of viral-induced pathologies.
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