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【报导】非结合态gp120的结构终于被解出
Nature 433, 834 - 841 (24 February 2005); doi:10.1038/nature03327
Structure of an unliganded simian immunodeficiency virus gp120 core
BING CHEN1, ERIK M. VOGAN1,2, HAIYUN GONG1, JOHN J. SKEHEL3, DON C. WILEY1,2,* & STEPHEN C. HARRISON1,2
1 Children's Hospital Laboratory of Molecular Medicine, Harvard Medical School, and
2 Howard Hughes Medical Institute, 320 Longwood Avenue, Boston, Massachusetts 02115, USA
3 National Institute of Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK
* Deceased
Correspondence and requests for materials should be addressed to S.C.H. (harrison@crystal.harvard.edu).
Coordinates and structure factors have been deposited in the PDB, accession number 2BF1.
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.
The envelope glycoproteins of HIV and SIV are the molecular agents of cell attachment and membrane fusion1. They are trimeric assemblies of gp160 polypeptide chains, which are cleaved during transport to the surface of an infected cell into two fragments known as gp120 and gp41 (refs 2–4). Cleavage enables the protein to undergo a series of conformational changes when it encounters the receptor for these viruses, CD4, and their co-receptor, CXCR4 or CCR5, on the surface of a suitable host cell5-8. The first of these changes, probably confined largely to gp120, accompanies receptor binding9, 10. It stabilizes a conformation with which a co-receptor can then associate7, 8, 11. Co-receptor binding may induce further changes, leading to dissociation of gp120 from the membrane-anchored gp41. The latter then refolds through a series of steps that lead ultimately to fusion of viral and target-cell membranes12, 13.
The structures of gp120 and gp41 at the end of this sequence of conformational changes have been determined in a series of X-ray crystallographic studies12-14. Analysis of the postfusion gp41 structure has been particularly important for deriving a picture of the fusion process and for understanding the mechanism of peptide fusion inhibitors13, 15, 16. The structure of CD4-bound, HIV-1 gp120, in complex with a monoclonal Fab that recognizes the co-receptor site, has provided a framework for analysing envelope antigenicity14, 17. The unliganded, prefusion structure of gp120 and the structure of the prefusion trimer (including the prefusion conformation of gp41) have resisted high-resolution analysis.
The structure of SIV gp120 in an unliganded conformation, described here, now fills one of those lacunae. As in the studies of the CD4-bound structure14, we have used the gp120 'core', from which two large loops of highly variable sequence, V1–V2 and V3, as well as amino- and carboxy-terminal segments, have been deleted (Fig. 1a). Comparison of the new structure of unliganded gp120 with that of the CD4-bound protein shows that part of the molecule—the 'inner domain' (see below)—undergoes unexpectedly extensive conformational rearrangement upon receptor binding. In the process, coherent sites assemble for CD4 and co-receptor interaction. Because the protein we have crystallized is fully glycosylated, we can visualize directly the extent to which oligosaccharides coat its molecular surface. Knowledge of the unliganded conformation allows us to model how the protein might appear in a gp120/gp41 trimer and to picture the overall conformational change induced by contact with receptor.
Figure 1 Structure and sequence of SIV gp120 core. Full legend
High resolution image and legend (108k)
Crystallization of the unliganded SIV gp120 core
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作者:admin@医学,生命科学 2011-05-08 05:14
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