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PDBsum entry 3ixt
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Immune system
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PDB id
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3ixt
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Contents |
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211 a.a.
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213 a.a.
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26 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 basis of respiratory syncytial virus neutralization by motavizumab.
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Authors
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J.S.Mclellan,
M.Chen,
A.Kim,
Y.Yang,
B.S.Graham,
P.D.Kwong.
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Ref.
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Nat Struct Biol, 2010,
17,
248-250.
[DOI no: ]
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PubMed id
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Abstract
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Motavizumab is approximately tenfold more potent than its predecessor,
palivizumab (Synagis), the FDA-approved monoclonal antibody used to prevent
respiratory syncytial virus (RSV) infection. The structure of motavizumab in
complex with a 24-residue peptide corresponding to its epitope on the RSV fusion
(F) glycoprotein reveals the structural basis for this greater potency. Modeling
suggests that motavizumab recognizes a different quaternary configuration of the
F glycoprotein than that observed in a homologous structure.
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Figure 1.
(a) RSV neutralization curves for palivizumab and motavizumab
IgG as determined by a flow cytometric assay. (b) Surface
representation of the Fab and ribbon representation of the
peptide, viewed looking down at the CDRs and a 90° rotation
about the horizontal axis from c and d. (c) Interactions between
the peptide and six Fab CDRs. Side chains are shown for those
residues making intermolecular interactions. Dashed lines
represent hydrogen bonds. Residues in the hydrophobic patch on
the heavy chain are shown with transparent surfaces. These
include Trp52 and Trp53 on the right and Ile97, Phe98 and Phe100
on the left. (d) Motavizumab mutations that alter affinity to
the F glycoprotein. Side chains are shown for those Fab residues
that increase affinity by directly contacting the peptide (red),
by altering the position of residues that directly contact the
peptide (cyan) or by binding to the F glycoprotein outside the
primary epitope or enhancing long-range electrostatic
interactions (magenta). Fab residues in yellow decrease the
affinity for the F glycoprotein but increase in vivo potency
compared to an earlier version of motavizumab.
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Figure 2.
(a) Superposition of the motavizumab-bound peptide (gray) and
residues 229–252 of the PIV5 F glycoprotein structure (red).
(b) Ribbon representation of the model of motavizumab Fab (green
and blue) bound to the PIV5 F glycoprotein monomer (tan) via the
superposition shown in a. (c) Same as b, except the entire PIV5
F glycoprotein trimer is shown (tan, green, pink). (d)
Magnification of the boxed area shown in c. (e) Gel filtration
elution profile and corresponding Coomassie blue–stained
SDS-PAGE gel of the RSV F[0] Fd glycoprotein. (f) Gel filtration
elution profile and corresponding Coomassie blue–stained
SDS-PAGE gel of a mixture of RSV F[0] Fd glycoprotein and excess
palivizumab Fab. Densitometric analysis of the gel yields a
ratio of 2.97 Fabs per trimer.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Struct Biol
(2010,
17,
248-250)
copyright 2010.
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