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Structure of an unliganded simian immunodeficiency virus gp120 core

Nature volume 433, pages 834–841 (2005)Cite this article

Abstract

Envelope glycoproteins of human and simian immunodeficiency virus (HIV and SIV) undergo a series of conformational changes when they interact with receptor (CD4) and co-receptor on the surface of a potential host cell, leading ultimately to fusion of viral and cellular membranes. Structures of fragments of gp120 and gp41 from the envelope protein are known, in conformations corresponding to their post-attachment and postfusion states, respectively. We report the crystal structure, at 4 Å resolution, of a fully glycosylated SIV gp120 core, in a conformation representing its prefusion state, before interaction with CD4. Parts of the protein have a markedly different organization than they do in the CD4-bound state. Comparison of the unliganded and CD4-bound structures leads to a model for events that accompany receptor engagement of an envelope glycoprotein trimer. The two conformations of gp120 also present distinct antigenic surfaces. We identify the binding site for a compound that inhibits viral entry.

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Figure 1: Structure and sequence of SIV gp120 core.
Figure 2: Comparison of glycosylated, unliganded SIV gp120 core with deglycosylated, liganded HIV-1 HXBc2 gp120 core14.
Figure 3: Conformational changes induced by CD4 binding.
Figure 4: The binding sites (BS) of CD4 and monoclonal antibody (mAb) 17b (ref. 14), and the putative binding site of BMS-378806 (ref. 24), a small-molecule inhibitor of HIV-1 entry.
Figure 5: Surface structure of the glycosylated, unliganded gp120 core.
Figure 6: Proposed models for gp120/gp41 trimers in unliganded and CD4-bound conformations.

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Acknowledgements

We thank staff at CHESS beamline F1 and APS beamline 19ID for assistance, J. Hoxie of University of Pennsylvania, for hybridomas, and members of the Harrison/Wiley laboratory for discussion. The research was supported by a Scholar Award from the American Foundation for AIDS Research (to B.C.), by the NIH Innovation Grant Program for Approaches in HIV Vaccine Research (to S.C.H. and D.C.W.), and by an NIH HIVRAD grant (to Ellis Reinherz). S.C.H. is, and D.C.W. was, an Investigator of the Howard Hughes Medical Institute.

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  1. Don C. Wiley: Deceased

Authors and Affiliations

  1. Children's Hospital Laboratory of Molecular Medicine, Harvard Medical School,

    Bing Chen, Erik M. Vogan, Haiyun Gong, Don C. Wiley & Stephen C. Harrison

  2. Howard Hughes Medical Institute, 320 Longwood Avenue, Boston, Massachusetts, 02115, USA

    Erik M. Vogan, Don C. Wiley & Stephen C. Harrison

  3. National Institute of Medical Research, The Ridgeway, London Mill Hill, NW7 1AA, UK

    John J. Skehel

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Supplementary Figure S1

Analysis by native polyacrylamide gel eletrophoresis of complexes of SIV gp120 core and Fab fragments from a panel of neutralizing monoclonal antibodies. (DOC 87 kb)

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Chen, B., Vogan, E., Gong, H. et al. Structure of an unliganded simian immunodeficiency virus gp120 core. Nature 433, 834–841 (2005). https://doi.org/10.1038/nature03327

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