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PDBsum entry 3bkj
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Immune system
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PDB id
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3bkj
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References listed in PDB file
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Key reference
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Title
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Amyloid-Beta-Anti-Amyloid-Beta complex structure reveals an extended conformation in the immunodominant b-Cell epitope.
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Authors
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L.A.Miles,
K.S.Wun,
G.A.Crespi,
M.T.Fodero-Tavoletti,
D.Galatis,
C.J.Bagley,
K.Beyreuther,
C.L.Masters,
R.Cappai,
W.J.Mckinstry,
K.J.Barnham,
M.W.Parker.
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Ref.
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J Mol Biol, 2008,
377,
181-192.
[DOI no: ]
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PubMed id
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Abstract
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Alzheimer's disease (AD) is the most common form of dementia. Amyloid-beta (A
beta) peptide, generated by proteolytic cleavage of the amyloid precursor
protein, is central to AD pathogenesis. Most pharmaceutical activity in AD
research has focused on A beta, its generation and clearance from the brain. In
particular, there is much interest in immunotherapy approaches with a number of
anti-A beta antibodies in clinical trials. We have developed a monoclonal
antibody, called WO2, which recognises the A beta peptide. To this end, we have
determined the three-dimensional structure, to near atomic resolution, of both
the antibody and the complex with its antigen, the A beta peptide. The
structures reveal the molecular basis for WO2 recognition and binding of A beta.
The A beta peptide adopts an extended, coil-like conformation across its major
immunodominant B-cell epitope between residues 2 and 8. We have also studied the
antibody-bound A beta peptide in the presence of metals known to affect its
aggregation state and show that WO2 inhibits these interactions. Thus,
antibodies that target the N-terminal region of A beta, such as WO2, hold
promise for therapeutic development.
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Figure 1.
Fig. 1. C^α-trace representations of WO2. (a) Ribbon
pictures of unliganded WO2 Fab variable domain structures after
superimposition of their C^α atoms. Form A is in yellow and
Form B is in green. (b) Stereo representation of Aβ in the WO2
Fab variable domain CDRs after superimposition of their C^α
atoms. The unliganded Form A is in yellow and the complex with
Aβ[1–16] is in blue. The Aβ[1–16] peptide is shown as
ball-and-stick.
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Figure 2.
Fig. 2. Surface representation of the WO2 antibody CDRs in
complex with Aβ[1–16]. Highlighted in colour are residues
from the CDRs that closely contact with Aβ: L1 (red), L3
(lemon), H2 (light blue) and H3 (orange). The Aβ peptide is
shown as ball-and-stick.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2008,
377,
181-192)
copyright 2008.
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