Structural biology of host factors affecting retroviral integration

National Institute Of Diabetes And Digestive And Kidney Diseases

Investigators

Linked publications & trials

Abstract

It has become increasingly clear that an important host cell protein involved in retroviral integration is lens-epithelium-derived growth factor (LEDGF/p75), a transcriptional coactivator that has been shown to influence target site selection by HIV integrase (Ciuffi et al., 2005; Llano et al., 2006). LEDGF interacts directly with HIV integrase, and has been proposed to act as a tether that links pre-integration complexes to chromatin. Recently, the co-crystal structure of the integrase-binding region of LEDGF and the catalytic domain of HIV integrase has been determined (Cherepanov et al., 2005). However, it is not yet understood how LEDGF interacts with chromatin and directs integrase to its site of action. We have focused our structural attention on the N-terminal domain of LEDGF, a member of the PWWP family of proteins. This N-terminal domain has been hypothesized to bind to naked DNA but recent data suggests that it may may bind to other chromatin elements (Botbol et al., 2008). We have expressed and purified several constructs encompassing this domain, and crystallization trials with DNA and chromatin-associated factors are underway.[unreadable] [unreadable] Botbol, Y., Raghavendra, N.K., Rahman, S., Engelman, A., and Lavigne, M. (2008) Nucleic Acids Res. 36, 1237-1246.[unreadable] Cherepanov, P., Ambrosio, A.L.B., Rahman, S., Ellenberger, T., and Engelman, A. (2005) Proc. Natl. Acad. Sci. USA 102, 17308-17313.[unreadable] Ciuffi, A., et al. (2005) Nature Med. 11, 1287-1289.[unreadable] Llano, M., et al. (2006) Science 314, 461-464.