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      Structural definition of a conserved neutralization epitope on HIV-1 gp120

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          Abstract

          The remarkable diversity, glycosylation and conformational flexibility of the human immunodeficiency virus type 1 (HIV-1) envelope (Env), including substantial rearrangement of the gp120 glycoprotein upon binding the CD4 receptor, allow it to evade antibody-mediated neutralization. Despite this complexity, the HIV-1 Env must retain conserved determinants that mediate CD4 binding. To evaluate how these determinants might provide opportunities for antibody recognition, we created variants of gp120 stabilized in the CD4-bound state, assessed binding of CD4 and of receptor-binding-site antibodies, and determined the structure at 2.3 Å resolution of the broadly neutralizing antibody b12 in complex with gp120. b12 binds to a conformationally invariant surface that overlaps a distinct subset of the CD4-binding site. This surface is involved in the metastable attachment of CD4, before the gp120 rearrangement required for stable engagement. A site of vulnerability, related to a functional requirement for efficient association with CD4, can therefore be targeted by antibody to neutralize HIV-1.

          Supplementary information

          The online version of this article (doi:10.1038/nature05580) contains supplementary material, which is available to authorized users.

          HIV's hidden weakness

          Human immunodeficiency virus type 1 (HIV-1) evades host defences thanks to its protective layers of immune camouflage. But b12 antibody pierces these barriers, so its interactions with HIV's gp120 envelope glycoprotein are of interest to vaccine and drug designers. The conformational flexibility of gp120 complicates analysis, but this obstacle has been overcome by using gp120 molecules stabilized in the CD4-bound state. Biophysical analysis with these 'frozen' gp120s shows receptor binding to occur in two steps: an initial 'handshake' followed by a shape-shifting 'bear hug'. The antibody by-passes gp120's protective shape shifting by exploiting an unexpected vulnerability of the handshake: the need for a substantial 'onrate' to efficiently engage CD4. The cover X-ray crystallographic image catches b12 antibody (green) as it grabs onto this newly identified site of vulnerability (yellow).

          Supplementary information

          The online version of this article (doi:10.1038/nature05580) contains supplementary material, which is available to authorized users.

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          Most cited references 31

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          Core structure of gp41 from the HIV envelope glycoprotein.

          The envelope glycoprotein of human immunodeficiency virus type 1 (HIV-1) consists of a complex of gp120 and gp41. gp120 determines viral tropism by binding to target-cell receptors, while gp41 mediates fusion between viral and cellular membranes. Previous studies identified an alpha-helical domain within gp41 composed of a trimer of two interacting peptides. The crystal structure of this complex, composed of the peptides N36 and C34, is a six-helical bundle. Three N36 helices form an interior, parallel coiled-coil trimer, while three C34 helices pack in an oblique, antiparallel manner into highly conserved, hydrophobic grooves on the surface of this trimer. This structure shows striking similarity to the low-pH-induced conformation of influenza hemagglutinin and likely represents the core of fusion-active gp41. Avenues for the design/discovery of small-molecule inhibitors of HIV infection are directly suggested by this structure.
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            Atomic structure of the ectodomain from HIV-1 gp41.

            Fusion of viral and cellular membranes by the envelope glycoprotein gp120/gp41 effects entry of HIV-1 into the cell. The precursor, gp160, is cleaved post-translationally into gp120 and gp41 which remain non-covalently associated. Binding to both CD4 and a co-receptor leads to the conformational changes in gp120/gp41 needed for membrane fusion. We used X-ray crystallography to determine the structure of the protease-resistant part of a gp41 ectodomain solubilized with a trimeric GCN4 coiled coil in place of the amino-terminal fusion peptide. The core of the molecule is found to be an extended, triple-stranded alpha-helical coiled coil with the amino terminus at its tip. A carboxy-terminal alpha-helix packs in the reverse direction against the outside of the coiled coil, placing the amino and carboxy termini near each other at one end of the long rod. These features, and the existence of a similar reversal of chain direction in the fusion pH-induced conformation of influenza virus HA2 and in the transmembrane subunit of Moloney murine leukaemia virus (Fig. 1a-d), suggest a common mechanism for initiating fusion.
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              AMoRe: an automated package for molecular replacement

               J. Navaza (1994)
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                Author and article information

                Contributors
                pdkwong@nih.gov
                Journal
                Nature
                Nature
                Nature
                Nature Publishing Group UK (London )
                0028-0836
                1476-4687
                2007
                : 445
                : 7129
                : 732-737
                Affiliations
                [1 ]Vaccine Research Center, and,, ,
                [2 ]GRID grid.419681.3, ISNI 0000 0001 2164 9667, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA, ; ,
                [3 ]GRID grid.214007.0, ISNI 0000000122199231, Departments of Immunology and Molecular Biology, , Scripps Research Institute, La Jolla, California 92037, USA, ; ,
                [4 ]Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA, ,
                [5 ]GRID grid.417768.b, ISNI 0000 0004 0483 9129, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, USA, ; ,
                Article
                BFnature05580
                10.1038/nature05580
                2584968
                17301785
                © Nature Publishing Group 2006

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

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