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Atomic-level modelling of the HIV capsid

Nature volume 469, pages 424–427 (2011)Cite this article

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Abstract

The mature capsids of human immunodeficiency virus type 1 (HIV-1) and other retroviruses are fullerene shells, composed of the viral CA protein, that enclose the viral genome and facilitate its delivery into new host cells1. Retroviral CA proteins contain independently folded amino (N)- and carboxy (C)-terminal domains (NTD and CTD) that are connected by a flexible linker2,3,4. The NTD forms either hexameric or pentameric rings, whereas the CTD forms symmetric homodimers that connect the rings into a hexagonal lattice3,5,6,7,8,9,10,11,12,13. We previously used a disulphide crosslinking strategy to enable isolation and crystallization of soluble HIV-1 CA hexamers11,14. Here we use the same approach to solve the X-ray structure of the HIV-1 CA pentamer at 2.5 Å resolution. Two mutant CA proteins with engineered disulphides at different positions (P17C/T19C and N21C/A22C) converged onto the same quaternary structure, indicating that the disulphide-crosslinked proteins recapitulate the structure of the native pentamer. Assembly of the quasi-equivalent hexamers and pentamers requires remarkably subtle rearrangements in subunit interactions, and appears to be controlled by an electrostatic switch that favours hexamers over pentamers. This study completes the gallery of substructures describing the components of the HIV-1 capsid and enables atomic-level modelling of the complete capsid. Rigid-body rotations around two assembly interfaces appear sufficient to generate the full range of continuously varying lattice curvature in the fullerene cone.

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Figure 1: Structure of the disulphide-stabilized HIV-1 CA pentamer and comparison with the hexamer.
Figure 2: Comparison of the pentamer and hexamer interactions.
Figure 3: Quasi-equivalence in the pentameric and hexameric NTD rings.
Figure 4: Model of the HIV-1 capsid.

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Accession codes

Primary accessions

Protein Data Bank

Data deposits

The coordinates and structure factors are deposited in Protein Data Bank under accession numbers 3P05 (N21C/A22C-stabilized pentamer) and 3P0A (P17C/T19C-stabilized pentamer). To reflect the limited resolution of the second structure properly, only Cα coordinates are deposited.

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Acknowledgements

This study was funded by grants from the US National Institutes of Health to M.Y. (R01-GM066087 and P50-GM082545). X-ray diffraction data were collected at beamlines 22-BM and 22-ID at the Advanced Photon Source, Argonne National Laboratory. Initial crystal screening was performed with the assistance of S. Banumathi through the Collaborative Crystallography Program, Lawrence Berkeley National Laboratory at the Advanced Light Source. We thank J. E. Johnson and D. Borek for crystallographic advice; Y. Hua for assistance with molecular biology experiments; and I. A. Wilson, C. P. Hill and W. I. Sundquist for critical reading of the manuscript.

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Authors and Affiliations

  1. Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, 22908, Virginia, USA

    Owen Pornillos, Barbie K. Ganser-Pornillos & Mark Yeager

  2. Department of Cell Biology, The Scripps Research Institute, La Jolla, 92037, California, USA

    Owen Pornillos, Barbie K. Ganser-Pornillos & Mark Yeager

  3. Division of Cardiovascular Medicine, Department of Medicine, University of Virginia Health System, Charlottesville, 22908, Virginia, USA

    Mark Yeager

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  1. Owen Pornillos
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Contributions

All authors designed/performed the experiments, analysed the data and wrote the manuscript. O.P. performed the computational aspects of crystallographic structure determination.

Corresponding author

Correspondence to Mark Yeager.

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The authors declare no competing financial interests.

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Pornillos, O., Ganser-Pornillos, B. & Yeager, M. Atomic-level modelling of the HIV capsid. Nature 469, 424–427 (2011). https://doi.org/10.1038/nature09640

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