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* Residue conservation analysis
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DOI no:
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J Mol Biol
377:181-192
(2008)
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PubMed id:
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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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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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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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Selected figure(s)
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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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Figures were
selected
by the author.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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A.Teplyakov,
G.Obmolova,
G.Canziani,
Y.Zhao,
L.Gutshall,
S.S.Jung,
and
G.L.Gilliland
(2011).
His-tag binding by antibody C706 mimics β-amyloid recognition.
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J Mol Recognit,
24,
570-575.
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PDB codes:
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G.S.Basi,
H.Feinberg,
F.Oshidari,
J.Anderson,
R.Barbour,
J.Baker,
T.A.Comery,
L.Diep,
D.Gill,
K.Johnson-Wood,
A.Goel,
K.Grantcharova,
M.Lee,
J.Li,
A.Partridge,
I.Griswold-Prenner,
N.Piot,
D.Walker,
A.Widom,
M.N.Pangalos,
P.Seubert,
J.S.Jacobsen,
D.Schenk,
and
W.I.Weis
(2010).
Structural correlates of antibodies associated with acute reversal of amyloid beta-related behavioral deficits in a mouse model of Alzheimer disease.
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J Biol Chem,
285,
3417-3427.
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PDB codes:
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P.H.Kuhn,
H.Wang,
B.Dislich,
A.Colombo,
U.Zeitschel,
J.W.Ellwart,
E.Kremmer,
S.Rossner,
and
S.F.Lichtenthaler
(2010).
ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons.
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EMBO J,
29,
3020-3032.
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R.Robert,
M.P.Lefranc,
A.Ghochikyan,
M.G.Agadjanyan,
D.H.Cribbs,
W.E.Van Nostrand,
K.L.Wark,
and
O.Dolezal
(2010).
Restricted V gene usage and VH/VL pairing of mouse humoral response against the N-terminal immunodominant epitope of the amyloid β peptide.
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Mol Immunol,
48,
59-72.
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R.Robert,
V.A.Streltsov,
J.Newman,
L.A.Pearce,
K.L.Wark,
and
O.Dolezal
(2010).
Germline humanization of a murine Abeta antibody and crystal structure of the humanized recombinant Fab fragment.
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Protein Sci,
19,
299-308.
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PDB code:
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A.Gardberg,
L.Dice,
K.Pridgen,
J.Ko,
P.Patterson,
S.Ou,
R.Wetzel,
and
C.Dealwis
(2009).
Structures of Abeta-related peptide--monoclonal antibody complexes.
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Biochemistry,
48,
5210-5217.
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PDB codes:
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R.Robert,
O.Dolezal,
L.Waddington,
M.K.Hattarki,
R.Cappai,
C.L.Masters,
P.J.Hudson,
and
K.L.Wark
(2009).
Engineered antibody intervention strategies for Alzheimer's disease and related dementias by targeting amyloid and toxic oligomers.
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Protein Eng Des Sel,
22,
199-208.
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K.S.Wun,
L.A.Miles,
G.A.Crespi,
K.Wycherley,
D.B.Ascher,
K.J.Barnham,
R.Cappai,
K.Beyreuther,
C.L.Masters,
M.W.Parker,
and
W.J.McKinstry
(2008).
Crystallization and preliminary X-ray diffraction analysis of the Fab fragment of WO2, an antibody specific for the Abeta peptides associated with Alzheimer's disease.
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Acta Crystallogr Sect F Struct Biol Cryst Commun,
64,
438-441.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
codes are
shown on the right.
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