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PDBsum entry 2nxz
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Viral protein/immune system
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PDB id
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2nxz
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Contents |
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306 a.a.
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181 a.a.
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214 a.a.
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222 a.a.
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References listed in PDB file
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Key reference
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Title
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Structural definition of a conserved neutralization epitope on HIV-1 gp120.
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Authors
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T.Zhou,
L.Xu,
B.Dey,
A.J.Hessell,
D.Van ryk,
S.H.Xiang,
X.Yang,
M.Y.Zhang,
M.B.Zwick,
J.Arthos,
D.R.Burton,
D.S.Dimitrov,
J.Sodroski,
R.Wyatt,
G.J.Nabel,
P.D.Kwong.
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Ref.
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Nature, 2007,
445,
732-737.
[DOI no: ]
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PubMed id
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Abstract
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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 A 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.
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Figure 2.
Figure 2: Conformational states of gp120. The unliganded,
b12- and CD4-bound conformations of gp120 are depicted, with
polypeptide in ribbon representation and disordered regions as
dashed lines. Inner domains are grey, outer domains are red and
regions that in the CD4-bound state correspond to the bridging
sheet are blue. Both b12- and CD4-bound conformations are of the
Ds12 F123 variant of HIV-1, whereas the unliganded structure is
of simian immunodeficiency virus (SIV). Comparison of these
three gp120 conformations highlights not only the structural
plasticity of the inner domain and bridging sheet, but also the
conformational stability of the outer domain.
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Figure 4.
Figure 4: Structural definition of a conformationally invariant,
antibody-accessible portion of the CD4-binding site. The b12-
and CD4-bound conformations of gp120 are shown in ribbon
representation, after superposition of outer domains (red). A
semitransparent molecular surface shows the contact surfaces of
b12 (green) and CD4 (yellow). Subsets of these surfaces,
corresponding to regions of conformational flexibility (for
example, of the inner domain (grey) or bridging sheet (blue)),
are delineated, as are regions of b12 contact outside of the
conserved CD4-binding site. As can be seen, functional analysis
serves to transcend the particulars of b12 binding, whereas
antibody defines accessibility. Although we have formally shown
only the b12 contact surface to be accessible in the context of
a functional viral spike, the highly effective neutralization of
D1D2-Ig  tp
and the kinetics of its association with both core and OD1
variants of gp120 suggest that the CD4-binding surface on the
outer domain is accessible.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nature
(2007,
445,
732-737)
copyright 2007.
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