Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2010 Jan 19;107(3):1166-71.
doi: 10.1073/pnas.0911004107. Epub 2009 Dec 28.

Structure of HIV-1 gp120 with gp41-interactive region reveals layered envelope architecture and basis of conformational mobility

Marie Pancera  1 , Shahzad Majeed, Yih-En Andrew Ban, Lei Chen, Chih-chin Huang, Leopold Kong, Young Do Kwon, Jonathan Stuckey, Tongqing Zhou, James E Robinson, William R Schief, Joseph Sodroski, Richard Wyatt, Peter D Kwong
Affiliations

Structure of HIV-1 gp120 with gp41-interactive region reveals layered envelope architecture and basis of conformational mobility

Marie Pancera et al. Proc Natl Acad Sci U S A. .

Abstract

The viral spike of HIV-1 is composed of three gp120 envelope glycoproteins attached noncovalently to three gp41 transmembrane molecules. Viral entry is initiated by binding to the CD4 receptor on the cell surface, which induces large conformational changes in gp120. These changes not only provide a model for receptor-triggered entry, but affect spike sensitivity to drug- and antibody-mediated neutralization. Although some of the details of the CD4-induced conformational change have been visualized by crystal structures and cryoelectron tomograms, the critical gp41-interactive region of gp120 was missing from previous atomic-level characterizations. Here we determine the crystal structure of an HIV-1 gp120 core with intact gp41-interactive region in its CD4-bound state, compare this structure to unliganded and antibody-bound forms to identify structurally invariant and plastic components, and use ligand-oriented cryoelectron tomograms to define component mobility in the viral spike context. Newly defined gp120 elements proximal to the gp41 interface complete a 7-stranded beta-sandwich, which appeared invariant in conformation. Loop excursions emanating from the sandwich form three topologically separate--and structurally plastic--layers, topped off by the highly glycosylated gp120 outer domain. Crystal structures, cryoelectron tomograms, and interlayer chemistry were consistent with a mechanism in which the layers act as a shape-changing spacer, facilitating movement between outer domain and gp41-associated beta-sandwich and providing for conformational diversity used in immune evasion. A "layered" gp120 architecture thus allows movement among alternative glycoprotein conformations required for virus entry and immune evasion, whereas a beta-sandwich clamp maintains gp120-gp41 interaction and regulates gp41 transitions.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
 Structure of an HIV-1 gp120 core with intact gp41-interactive region. (A) Ternary complex: ribbon diagram shows previously described core gp120 (gray), with newly identified intact N terminus (red) and C terminus (purple), bound by the membrane-distal two domains of CD4 (yellow) and the antigen-binding fragment (Fab) of antibody 48d (light and dark blue). In this orientation, the viral membrane (and hence the gp41-transmembrane glycoprotein) would be positioned toward the top of the page and the target cell toward the bottom. (B) Close-up: core gp120 with intact gp41-interaction region is shown from a 90° view about a vertical axis from A. Coloring is the same as in A, except that the outer domain is orange. (C) Topology: the inner domain of gp120 is shown with β-strands as arrows and α-helices as coils; close strand proximity is indicative of hydrogen bonding. Coloring is the same as in B, with the bridging sheet (β2, β3, β20, β21) and extensions to the outer domain shown with dotted lines. (D) Sequence: the sequences of the crystallized clade B isolate (HXBc2), the consensus for HIV-1 group M (CONSENSUS M), and SIVmac239 (SIVMM239 MAC) are shown, with secondary structure as arrows (β-strand) and coils (α-helices). The gg sequence refers to the dipeptide truncation, gly-gly, which was used to replace the V1/V2 variable region. Regions of disorder are marked with an x, and outer domain (residues 257–472) is labeled. Blue boxes highlight residues that are involved in gp41 interaction, as defined by mutagenesis studies (–21). (E) Ribbon representation of gp120 as shown in B, with residues implicated by mutagenesis in the interaction with gp41 highlighted with blue spheres and sticks. (F) Placement of the gp120-CD4-Fab 17b complex in the electron density map derived from cryoelectron tomography (light gray) (6), with gp120 and residues involved in gp41 interactions colored as in E, and Fab 17b in light brown. (G) View of 90° rotation from F from the viral membrane.
Fig. 2.
Fig. 2.
“Layered” gp120 architecture: invariant β-sandwich and structurally plastic layers. (A) The newly defined 7-stranded β-sandwich is shown in ribbon diagram representation (red) with β-strands labeled and loop excursions to the layers depicted schematically. (B) Schematic representation of gp120 structure. (C) β-Sandwich superposition of the newly defined CD4-bound conformation of gp120 with unliganded and antibody-bound conformations, in two 90° orientations. Polypeptides are drawn in ribbon representations, with 7-stranded β-sandwich colored red, layer 1 in violet, layer 2 in cyan, layer 3 in blue, and the outer domain in light brown. (D) Different conformations of monomeric gp120 are shown in ribbon diagram representation. Note that layer 1 is present in only the CD4-bound form described here. Structural elements are colored the same as in C.
Fig. 3.
Fig. 3.
Conformational diversity of gp120. Protein motions can be classified into categories of hinge, shear, and refold (Left) (35). These archetypes show distinctive signatures when analyzed by enumerating secondary structure changes (horizontal axis) and by difference–distance maximum (vertical axis). Hinge motions generate large difference distances, although only a few residues refold (e.g., calmodulin, hemolysin, and transglutaminase). Shear motions show small changes with both metrics (e.g., citrate synthase and calpain). Refold motions, by contrast, show large changes with both metrics. Refolding is perhaps best epitomized by the transmembrane components of type 1 fusion machines (e.g., “F1” of parainfluenza virus, “HA2” of influenza A virus, and “gp2” of Ebola virus). This analysis shows how gp120 fits into the refold category when moving from unliganded state or between different states induced by receptor and/or antibody. In this it differs from the N-terminal components of other type 1 fusion proteins (e.g., “HA1” of influenza virus). When fixed by CD4 binding, however, these metrics indicate that primarily a single state is induced. [Like gp120, the ubiquitin-conformational ensemble (29) also forms a cluster, although one of much smaller magnitude than that of gp120; to clarify presentation, only a single point for a relatively divergent pair of ubiquitin conformations is displayed, with the ubiquitin cluster extending from this point to the origin.] Labels are italicized representations of structures for which the sequence identity is less than 40% between the two conformations.
Fig. 4.
Fig. 4.
 Mechanism for gp120 mobility, gp41 fixation, and immune evasion. β-Sandwich clamp and embracing N and C termini of gp120 are shown holding gp41 in a metastable state. The layers, meanwhile, can refold to position the relative orientations of three highly glycosylated components: β-sandwich, V1/V2 loops, and outer domain. In the unliganded state (Left), the glycan-bearing elements arrange to form an effective “glycan shield” that prevents recognition by most antibodies. In the CD4-bound state (Right), the layers organize with outer domain to form the high-affinity binding sites for CD4 and coreceptor.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Wyatt R, Sodroski J. The HIV-1 envelope glycoproteins: fusogens, antigens, and immunogens. Science. 1998;280:1884–1888. - PubMed
    1. Moore JP, McKeating JA, Weiss RA, Sattentau QJ. Dissociation of gp120 from HIV-1 virions induced by soluble CD4. Science. 1990;250:1139–1142. - PubMed
    1. Haim H, et al. Soluble CD4 and CD4-mimetic compounds inhibit HIV-1 infection by induction of a short-lived activated state. PLoS Pathog. 2009;5:e1000360. - PMC - PubMed
    1. Chen B, et al. Structure of an unliganded simian immunodeficiency virus gp120 core. Nature. 2005;433:834–841. - PubMed
    1. Kwong PD, et al. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature. 1998;393:648–659. - PMC - PubMed

Publication types

Substances