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Accueil du site > Animations Scientifiques > Séminaires 2010 > Marc Ruff — Structural and functional role of ini1, a cellular cofactor of hiv-1 integrase in the early step of hiv infection

Marc Ruff — Structural and functional role of ini1, a cellular cofactor of hiv-1 integrase in the early step of hiv infection

Speaker :

Marc Ruff, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch

When :

Wednesday 1 December at 11am

Where :

C023 (RDC LR6 côté Centre Blaise Pascal)

Title :

Structural and functional role of ini1, a cellular cofactor of hiv-1 integrase in the early step of hiv infection

Abstract :

Integration of the human immunodeficiency virus type 1 (HIV-1) cDNA into the human genome is catalyzed by the viral integrase protein (IN) that requires cellular cofactors for viral infectivity. IN catalyzes a two step reaction, first the 3’ processing removes two nucleotides on the 3’ end of the viral DNA and second the strand transfer reaction performs the integration. A cryo-EM structure at 14 Å resolution of the HIV-1 integrase in complex with the lens epithelium-derived growth factor (LEDGF) has been solved in presence and absence of DNA (1). Recently we solve a cryo-EM structure of the ternary complex of HIV-1 Integrase, LEDGF and the integrase binding domain of the integrase interactor 1 protein (INI1) in absence (16 Å) and presence (18 Å) of DNA. In vitro functional and binding assays using fluorescence anisotropy have been performed showing the effect of INI1 on DNA binding and on the first catalytic activity of integrase, the 3’processing. We show that INI1 decreases the affinity of viral DNA for the IN/LEDGF complex by a factor of 2 and inhibits completely the 3’processing reaction. The structure shows that INI1 prevent the viral DNA to access the catalytic site of integrase. The functional role of INI1 could be to prevent the auto integration of the viral DNA. Theses structures could led the basis for the design of 3’processing inhibitors.

(1) Michel, F., Crucifix, C., Granger, F., Eiler, S., Mouscadet, J.F., Korolev, S., Agapkina, J., Ziganshin, R., Gottikh , M., Nazabal, A., Emiliani, S., Benarous, R., Moras, D., Schultz, P. and Ruff, M. (2009). Structural basis for HIV-1 DNA integration in the human genome, role of the LEDGF/P75 cofactor. EMBO J., 28, 980-991.

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