Retroviral integrase (IN) functions within the intasome nucleoprotein complex to catalyze insertion of viral DNA into cellular chromatin. Using cryo-electron microscopy, we now visualize the functional maedi-visna lentivirus intasome at 4.9 angstrom resolution. The intasome comprises a homo-hexadecamer of IN with a tetramer-of-tetramers architecture featuring eight structurally distinct types of IN protomers supporting two catalytically competent subunits. The conserved intasomal core, previously observed in simpler retroviral systems, is formed between two IN tetramers, with a pair of C-terminal domains from flanking tetramers completing the synaptic interface. Our results explain how HIV-1 IN, which self-associates into higher-order multimers, can form a functional intasome, reconcile the bulk of early HIV-1 IN biochemical and structural data, and provide a lentiviral platform for design of HIV-1 IN inhibitors.

A supramolecular assembly mediates lentiviral DNA integration / A. Ballandras-Colas, D.P. Maskell, E. Serrao, J. Locke, P. Swuec, S.R. Jónsson, A. Kotecha, N.J. Cook, V.E. Pye, I.A. Taylor, V. Andrésdóttir, A.N. Engelman, A. Costa, P. Cherepanov. - In: SCIENCE. - ISSN 0036-8075. - 355:6320(2017), pp. 93-95. [10.1126/science.aah7002]

A supramolecular assembly mediates lentiviral DNA integration

P. Swuec;
2017

Abstract

Retroviral integrase (IN) functions within the intasome nucleoprotein complex to catalyze insertion of viral DNA into cellular chromatin. Using cryo-electron microscopy, we now visualize the functional maedi-visna lentivirus intasome at 4.9 angstrom resolution. The intasome comprises a homo-hexadecamer of IN with a tetramer-of-tetramers architecture featuring eight structurally distinct types of IN protomers supporting two catalytically competent subunits. The conserved intasomal core, previously observed in simpler retroviral systems, is formed between two IN tetramers, with a pair of C-terminal domains from flanking tetramers completing the synaptic interface. Our results explain how HIV-1 IN, which self-associates into higher-order multimers, can form a functional intasome, reconcile the bulk of early HIV-1 IN biochemical and structural data, and provide a lentiviral platform for design of HIV-1 IN inhibitors.
Catalytic Domain; Cryoelectron Microscopy; DNA, Viral; Drug Design; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Models, Molecular; Protein Domains; Static Electricity; Virus Assembly; Virus Integration; Multidisciplinary
Settore BIO/10 - Biochimica
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/618943
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