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The HIV-1 capsid protein C-terminal domain in complex with a virus assembly inhibitor

Nature Structural & Molecular Biology volume 12, pages 678–682 (2005)Cite this article

Abstract

Immature HIV particles bud from infected cells after assembly at the cytoplasmic side of cellular membranes. This assembly is driven by interactions between Gag polyproteins. Mature particles, each containing a characteristic conical core, are later generated by proteolytic maturation of Gag in the virion. The C-terminal domain of the HIV-1 capsid protein (C-CA) has been shown to contain oligomerization determinants essential for particle assembly. Here we report the 1.7-Å-resolution crystal structure of C-CA in complex with a peptide capable of inhibiting immature- and mature-like particle assembly in vitro. The peptide inserts as an amphipathic α-helix into a conserved hydrophobic groove of C-CA, resulting in formation of a compact five-helix bundle with altered dimeric interactions. This structure thus reveals the details of an allosteric site in the HIV capsid protein that can be targeted for antiviral therapy.

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Figure 1: Binding of the CAI peptide leads to formation of a five-helix bundle.
Figure 2: The CAI peptide fits into a conserved hydrophobic cavity of C-CA.
Figure 3: CAI binding alters the C-CA dimer interface.

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Acknowledgements

We thank H. Van Tilbeurgh for access to the robotized platform of the Yeast Structural Genomics Laboratory and J. Werner, P. Vachette and J. Janin for helpful discussions. This work was supported by the Agence Nationale pour la Recherche contre le SIDA, the Deutsche Forschungsgemeinschaft, the Centre National de la Recherche Scientifique, the Institut National de la Recherche Agronomique, the SESAME program of Région Ile-de-France and the French/German PROCOPE scientific exchange program.

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Authors and Affiliations

  1. Laboratoire de Virologie Moléculaire & Structurale, UMR 2472/1157 CNRS-INRA and IFR 115, Avenue de la Terrasse, Gif-sur-Yvette, 91198, Cedex, France

    François Ternois, Stéphane Duquerroy & Félix A Rey

  2. Department of Virology, Universitätsklinikum Heidelberg, Heidelberg, 69120, Germany

    Jana Sticht & Hans-Georg Kräusslich

  3. Virology Department, Institut Pasteur, 25 rue du Dr. Roux, Paris, 75015, France

    Félix A Rey

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  1. François Ternois
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  2. Jana Sticht
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  4. Hans-Georg Kräusslich
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Correspondence to Félix A Rey.

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Supplementary information

Supplementary Table 1

Buried surfaces at dimer and C-CA/CAI interfaces. (PDF 12 kb)

Supplementary Table 2

Dimer contacts and C-CA/CAI interactions. (PDF 20 kb)

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Ternois, F., Sticht, J., Duquerroy, S. et al. The HIV-1 capsid protein C-terminal domain in complex with a virus assembly inhibitor. Nat Struct Mol Biol 12, 678–682 (2005). https://doi.org/10.1038/nsmb967

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