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PDBsum entry 1yyl
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Viral protein/immune system
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PDB id
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1yyl
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Contents |
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301 a.a.
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214 a.a.
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229 a.a.
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27 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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Scorpion-Toxin mimics of cd4 in complex with human immunodeficiency virus gp120 crystal structures, Molecular mimicry, And neutralization breadth.
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Authors
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C.C.Huang,
F.Stricher,
L.Martin,
J.M.Decker,
S.Majeed,
P.Barthe,
W.A.Hendrickson,
J.Robinson,
C.Roumestand,
J.Sodroski,
R.Wyatt,
G.M.Shaw,
C.Vita,
P.D.Kwong.
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Ref.
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Structure, 2005,
13,
755-768.
[DOI no: ]
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PubMed id
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Abstract
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The binding surface on CD4 for the HIV-1 gp120 envelope glycoprotein has been
transplanted previously onto a scorpion-toxin scaffold. Here, we use X-ray
crystallography to characterize atomic-level details of gp120 with this
transplant, CD4M33. Despite known envelope flexibility, the conformation of
gp120 induced by CD4M33 was so similar to that induced by CD4 that localized
measures were required to distinguish ligand-induced differences from lattice
variation. To investigate relationships between structure, function, and
mimicry, an F23 analog of CD4M33 was devised. Structural and thermodynamic
analyses showed F23 to be a better molecular mimic of CD4 than CD4M33. F23 also
showed increased neutralization breadth, against diverse isolates of HIV-1,
HIV-2, and SIVcpz. Our results lend insight into the stability of the CD4 bound
conformation of gp120, define measures that quantify molecular mimicry as a
function of evolutionary distance, and suggest how such evaluations might be
useful in developing mimetic antagonists with increased neutralization breadth.
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Figure 1.
Figure 1. Mimicry of CD4 by CD4M33
(A) Ribbon diagrams
of core YU2 gp120 (green) are shown binding to CD4 (left) and
CD4M33 (right). In this orientation, the four-stranded bridging
sheet of gp120 is positioned directly to the left of CD4, the
inner domain is positioned above it, and the outer domain is
positioned to the right. CD4M33 is shown in purple, and CD4 is
shown in gray, except for the three main regions that contribute
to binding, which are colored orange-yellow (residues 40-48) and
black (residues 31-35 and 58-64).
(B) Close-up view of the
CD4-gp120 "hotspot." The orientation and colors are the same as
in (A), except that oxygen atoms are colored red and nitrogen
atoms are colored blue. The unusual interfacial cavity (red)
between CD4 and gp120 is shown in the left panel. The right
panel shows the biphenyl side chain of CD4M33 reaching into the
heart of gp120. Density (F[o] - F[c]; 3 s; purple) is shown from
a simulated annealing omit map in which the entire CD4M33 had
been removed. Distances (Å) are shown for four hydrogen bonds.
(C) Close-up view of an intermolecular salt bridge. The
left panel shows the double hydrogen bond made by CD4 Arg 59.
The right panel displays the two independent CD4M33 complexes of
the P2[1] asymmetric unit (purple and gray), only one of which
makes a salt bridge with gp120.
(D) Contact surface on
gp120. The orientation shown is rotated 90° about a horizontal
axis from that shown in (A) and (B). In this orientation, the
virus would be located toward the top of the page, and the
target cell would be located toward the bottom. The left panel
shows the contact surface of CD4, colored green, with yellow
highlighting the portion of the surface contacted by CD4
residues 40-47. The right panel shows the contact surface of
CD4M33 in green, with purple highlighting the portion of the
surface contributed by CD4M33 residues 20-27. The portion of the
contact surface unique to CD4M33 (primarily where the biphenyl
moiety reaches into gp120) is highlighted in red.
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The above figure is
reprinted
by permission from Cell Press:
Structure
(2005,
13,
755-768)
copyright 2005.
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