A supramolecular assembly mediates lentiviral DNA integration

Allison Ballandras-Colas; Daniel P Maskell; Erik Serrao; Julia Locke; Paolo Swuec; Stefán R Jónsson; Abhay Kotecha; Nicola J Cook; Valerie E Pye; Ian A Taylor; Valgerdur Andrésdóttir; Alan N Engelman; Alessandro Costa; Peter Cherepanov

doi:10.1126/science.aah7002

A supramolecular assembly mediates lentiviral DNA integration

Science. 2017 Jan 6;355(6320):93-95. doi: 10.1126/science.aah7002.

Authors

Allison Ballandras-Colas^#¹, Daniel P Maskell^#¹, Erik Serrao^{2

3}, Julia Locke⁴, Paolo Swuec⁴, Stefán R Jónsson⁵, Abhay Kotecha⁶, Nicola J Cook¹, Valerie E Pye¹, Ian A Taylor⁷, Valgerdur Andrésdóttir⁵, Alan N Engelman^{2

3}, Alessandro Costa⁴, Peter Cherepanov^{1

8}

Affiliations

¹ Chromatin Structure and Mobile DNA, The Francis Crick Institute, London, NW1 1AT, UK.
² Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
³ Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
⁴ Macromolecular Machines Laboratory, The Francis Crick Institute, London, NW1 1AT, UK.
⁵ Institute for Experimental Pathology, University of Iceland, Keldur, 112 Reykjavik, Iceland.
⁶ Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.
⁷ Macromolecular Structure Laboratory, The Francis Crick Institute, London, NW1 1AT, UK.
⁸ Division of Medicine, Imperial College London, W2 1PG, UK.

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Catalytic Domain
Cryoelectron Microscopy
DNA, Viral / chemistry
DNA, Viral / ultrastructure
Drug Design
HIV Integrase / chemistry*
HIV Integrase / ultrastructure
HIV Integrase Inhibitors / chemistry
HIV-1 / chemistry*
HIV-1 / enzymology
HIV-1 / ultrastructure
Humans
Models, Molecular
Protein Domains
Static Electricity
Virus Assembly
Virus Integration*

Substances

DNA, Viral
HIV Integrase Inhibitors
HIV Integrase
p31 integrase protein, Human immunodeficiency virus 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding