title: A supramolecular assembly mediates lentiviral DNA integration.
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.
authors.affiliation: Chromatin Structure and Mobile DNA, The Francis Crick Institute, London, NW1 1AT, UK.
authors.forename: Allison
authors.initials: A
authors.lastname: Ballandras-Colas
authors.affiliation: Chromatin Structure and Mobile DNA, The Francis Crick Institute, London, NW1 1AT, UK.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Maskell
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.|Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Erik
authors.initials: E
authors.lastname: Serrao
authors.affiliation: Macromolecular Machines Laboratory, The Francis Crick Institute, London, NW1 1AT, UK.
authors.forename: Julia
authors.initials: J
authors.lastname: Locke
authors.affiliation: Macromolecular Machines Laboratory, The Francis Crick Institute, London, NW1 1AT, UK.
authors.forename: Paolo
authors.initials: P
authors.lastname: Swuec
authors.affiliation: Institute for Experimental Pathology, University of Iceland, Keldur, 112 Reykjavik, Iceland.
authors.forename: Stefán R
authors.initials: SR
authors.lastname: Jónsson
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.
authors.forename: Abhay
authors.initials: A
authors.lastname: Kotecha
authors.affiliation: Chromatin Structure and Mobile DNA, The Francis Crick Institute, London, NW1 1AT, UK.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Cook
authors.affiliation: Chromatin Structure and Mobile DNA, The Francis Crick Institute, London, NW1 1AT, UK.
authors.forename: Valerie E
authors.initials: VE
authors.lastname: Pye
authors.affiliation: Macromolecular Structure Laboratory, The Francis Crick Institute, London, NW1 1AT, UK.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Taylor
authors.affiliation: Institute for Experimental Pathology, University of Iceland, Keldur, 112 Reykjavik, Iceland.
authors.forename: Valgerdur
authors.initials: V
authors.lastname: Andrésdóttir
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.|Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Alan N
authors.initials: AN
authors.lastname: Engelman
authors.affiliation: Macromolecular Machines Laboratory, The Francis Crick Institute, London, NW1 1AT, UK.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Costa
authors.affiliation: Chromatin Structure and Mobile DNA, The Francis Crick Institute, London, NW1 1AT, UK.|Division of Medicine, Imperial College London, W2 1PG, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Cherepanov
mesh_terms: D020134:Catalytic Domain; D020285:Cryoelectron Microscopy; D004279:DNA, Viral / Q000737:chemistry / Q000648:ultrastructure; D015195:Drug Design; D019427:HIV Integrase / Q000737:chemistry* / Q000648:ultrastructure; D019428:HIV Integrase Inhibitors / Q000737:chemistry; D015497:HIV-1 / Q000737:chemistry* / Q000201:enzymology / Q000648:ultrastructure; D006801:Humans; D008958:Models, Molecular; D000072417:Protein Domains; D055672:Static Electricity; D019065:Virus Assembly; D016662:Virus Integration
chemical_list: D004279:DNA, Viral; D019428:HIV Integrase Inhibitors; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1