A supramolecular assembly mediates lentiviral DNA integration

• Published in: Science (American Association for the Advancement of Science) Vol. 355; no. 6320; pp. 93 - 95
• Main Authors: Ballandras-Colas, Allison, Maskell, Daniel P., Serrao, Erik, Locke, Julia, Swuec, Paolo, Jónsson, Stefán R., Kotecha, Abhay, Cook, Nicola J., Pye, Valerie E., Taylor, Ian A., Andrésdóttir, Valgerdur, Engelman, Alan N., Costa, Alessandro, Cherepanov, Peter
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 06.01.2017; The American Association for the Advancement of Science; American Association for the Advancement of Science (AAAS)
• Subjects: Assembly; Biochemistry; Catalytic Domain; Chromatin; Cryoelectron Microscopy; Deoxyribonucleic acid; Design engineering; DNA; DNA structure; DNA, Viral - chemistry; DNA, Viral - ultrastructure; Drug Design; Electron microscopy; Genomes; HIV; HIV Integrase - chemistry; HIV Integrase - ultrastructure; HIV Integrase Inhibitors - chemistry; HIV-1 - chemistry; HIV-1 - enzymology; HIV-1 - ultrastructure; Human immunodeficiency virus; Humans; Infections; Insertion; Integrase; Integration; Lentivirus; Life cycle engineering; Life cycles; Life Sciences; Maedi; Maedi-visna virus; Models, Molecular; Platforms; Protein Domains; Retroviridae; Static Electricity; Transmission electron microscopy; Virus Assembly; Virus Integration; Viruses; Visna
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aah7002

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.