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PDBsum entry 1jpt
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Immune system
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PDB id
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1jpt
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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The 1.85 a resolution crystal structures of tissue factor in complex with humanized FAB d3h44 and of free humanized FAB d3h44: revisiting the solvation of antigen combining sites.
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Authors
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K.Faelber,
D.Kirchhofer,
L.Presta,
R.F.Kelley,
Y.A.Muller.
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Ref.
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J Mol Biol, 2001,
313,
83-97.
[DOI no: ]
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PubMed id
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Abstract
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The outstanding importance of the antigen-antibody recognition process for the
survival and defence strategy of higher organisms is in sharp contrast to the
limited high resolution structural data available on antibody-antigen pairs with
antigenic proteins. The limitation is the most severe for structural data not
restricted to the antigen-antibody complex but extending to the uncomplexed
antigen and antibody. We report the crystal structure of the complex between
tissue factor (TF) and the humanized Fab fragment D3h44 at a resolution of 1.85
A together with the structure of uncomplexed D3h44 at the same resolution. In
conjunction with the previously reported 1.7 A crystal structure of uncomplexed
TF, a unique opportunity is generated to explore details of the recognition
process. The TF.D3h44 interface is characterised by a high number of polar
interactions, including as may as 46 solvent molecules. Conformational changes
upon complex formation are very small and almost exclusively limited to the
reorientation of side-chains. The binding epitope is in complete agreement with
earlier mutagenesis experiments. A revaluation of two other antibody-antigen
pairs reported at similar resolutions, shows that all these complexes are very
similar with respect to the solvation of the interface, the number of solvent
positions conserved in the uncomplexed and complexed proteins and the number of
water molecules expelled from the surface and replaced by hydrophilic atoms from
the binding partner upon complex formation. A strategy is proposed on how to
exploit this high resolution structural data to guide the affinity maturation of
humanised antibodies.
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Figure 1.
Figure 1. Ribbon representation of TF (in red) in complex
with D3h44 (light chain in light blue and heavy chain in dark
blue). D3h44 recognizes a binding epitope located in the
C-terminal FNIII domain of the ectodomain of TF. The b-strands
of the C-terminal FNIII domain of TF are labeled as established
for the topologically similar C2-type immunoglobulins.[34 and
35] This figure and all following model illustrations have been
prepared with program MOLMOL. [61]
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Figure 5.
Figure 5. Stereo representation of the highly complementary
hydrophilic interaction patch centered on Asp-H52. The TF
backbone is shown in red and the backbone of the CDRs from the
heavy chain in dark blue.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2001,
313,
83-97)
copyright 2001.
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Secondary reference #1
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Title
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Generation of a humanized, High affinity anti-Tissue factor antibody for use as a novel antithrombotic therapeutic.
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Authors
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L.Presta,
P.Sims,
Y.G.Meng,
P.Moran,
S.Bullens,
S.Bunting,
J.Schoenfeld,
D.Lowe,
J.Lai,
P.Rancatore,
M.Iverson,
A.Lim,
V.Chisholm,
R.F.Kelley,
M.Riederer,
D.Kirchhofer.
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Ref.
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Thromb Haemost, 2001,
85,
379-389.
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PubMed id
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