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Prefusion structure of trimeric HIV-1 envelope glycoprotein determined by cryo-electron microscopy

Nature Structural & Molecular Biology volume 20, pages 13521357 (2013) | Download Citation

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Abstract

The activation of trimeric HIV-1 envelope glycoprotein (Env) by its binding to the cell-surface receptor CD4 and co-receptors (CCR5 or CXCR4) represents the first of a series of events that lead to fusion between viral and target-cell membranes. Here, we present the cryo-EM structure, at subnanometer resolution (6 Å at 0.143 FSC), of the 'closed', prefusion state of trimeric HIV-1 Env complexed to the broadly neutralizing antibody VRC03. We show that three gp41 helices at the core of the trimer serve as an anchor around which the rest of Env is reorganized upon activation to the 'open' quaternary conformation. The architecture of trimeric HIV-1 Env in the prefusion state and in the activated intermediate state resembles the corresponding states of influenza hemagglutinin trimers, thus providing direct evidence for the similarity in entry mechanisms used by HIV-1, influenza and related enveloped viruses.

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  • 10 November 2013

    In the version of this article initially published online, the NIH-FEI Living Lab for Structural Biology was not mentioned in the Acknowledgments section. The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

This work was supported by funds to S.S. and J.L.S.M. from the Center for Cancer Research at the National Cancer Institute, US National Institutes of Health (NIH), and to S.S. from the NIH Intramural AIDS Targeted Antiviral Program. We thank J. Mascola (Vaccine Research Center, NIH) for providing VRC03 antibodies; K. Kang and W. Olson (Progenics) for providing soluble KNH1144 gp140 trimers; S. Fellini, S. Chacko and their colleagues for continued support with use of the Biowulf cluster for computing at NIH; D. Schauder and H. He for assistance with data collection; P. Rao and the NIH-FEI Living Lab for Structural Biology for assistance with collection of the tilt-pair images; and L. Earl for helpful discussions and comments.

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  1. Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

    • Alberto Bartesaghi
    • , Alan Merk
    • , Mario J Borgnia
    • , Jacqueline L S Milne
    •  & Sriram Subramaniam

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Contributions

A.B., A.M., M.J.B., J.L.S.M. and S.S. analyzed and interpreted data; S.S. was responsible for data collection; all authors helped compose the manuscript.

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The authors declare no competing financial interests.

Corresponding author

Correspondence to Sriram Subramaniam.

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https://doi.org/10.1038/nsmb.2711

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