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PDBsum entry 1nqb
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Immunoglobulin
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PDB id
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1nqb
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Contents |
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* Residue conservation analysis
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DOI no:
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Proc Natl Acad Sci U S A
94:9637-9642
(1997)
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PubMed id:
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The 2.0-A resolution crystal structure of a trimeric antibody fragment with noncognate VH-VL domain pairs shows a rearrangement of VH CDR3.
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X.Y.Pei,
P.Holliger,
A.G.Murzin,
R.L.Williams.
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ABSTRACT
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The 2.0-A resolution x-ray crystal structure of a novel trimeric antibody
fragment, a "triabody," has been determined. The trimer is made up of
polypeptides constructed in a manner identical to that previously described for
some "diabodies": a VL domain directly fused to the C terminus of a VH
domain-i.e., without any linker sequence. The trimer has three Fv heads with the
polypeptides arranged in a cyclic, head-to-tail fashion. For the particular
structure reported here, the polypeptide was constructed with a VH domain from
one antibody fused to the VL domain from an unrelated antibody giving rise to
"combinatorial" Fvs upon formation of the trimer. The structure shows
that the exchange of the VL domain from antibody B1-8, a Vlambda domain, with
the VL domain from antibody NQ11, a Vkappa domain, leads to a dramatic
conformational change in the VH CDR3 loop of antibody B1-8. The magnitude of
this change is similar to the largest of the conformational changes observed in
antibody fragments in response to antigen binding. Combinatorial pairing of VH
and VL domains constitutes a major component of antibody diversity.
Conformationally flexible antigen-binding sites capable of adapting to the
specific CDR3 loop context created upon VH-VL pairing may be employed by the
immune system to maximize the structural diversity of the immune response.
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Selected figure(s)
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Figure 4.
Fig. 4. A comparison of the V[L]-V[H] orientations of the
B1-8 (dashed lines) and B1-8/NQ11 (solid lines) Fvs. The C^  values
of the B1-8 V[H] framework were superimposed on the B1-8/NQ11^
V[H] framework. The C^ positions
of residues GlyH103 and TyrH106 are indicated by spheres (white
for B1-8 and black for B1-8/NQ11).
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Figure 5.
Fig. 5. Stereoview comparisons of the H3 loops in B1-8 and
B1-8/NQ11. (a) A worm representation of the H3 loop in B1-8
(shaded lighter) superimposed on the H3 loop of B1-8/NQ11
(shaded darker). The^ molecular surface shown is that of the
B1-8/NQ11 model with the^ H3 loop omitted. The surface of the
V[H] domain is white and the^ general surface of the V[L] domain
is light gray. The surface of^ Phe^L60 is shaded dark. The
analogous residue in B1-8 is Ala^L57 that leaves space to
accommodate the side chain of TyrH106 (shown in stick
representation) in the B1-8 Fv. The presence^ of GlyL96 (shaded)
leaves space to accommodate the side chain of TyrH106 in
B1-8/NQ11. The analogous volume in B1-8 is occupied by TrpL93.
(b) The H3 loop of B1-8/NQ11 and its interaction with V[  ]residues.
The C^ positions
are indicated with larger spheres. V[L] atoms are shown as white
spheres and V[H] atoms as black spheres. (c) The B1-8 H3^ loop
and its interactions with the V[  ]domain.
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Figures were
selected
by an automated process.
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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.R.Bradbury,
S.Sidhu,
S.Dübel,
and
J.McCafferty
(2011).
Beyond natural antibodies: the power of in vitro display technologies.
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Nat Biotechnol,
29,
245-254.
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C.Q.Bie,
D.H.Yang,
X.J.Liang,
and
S.H.Tang
(2010).
Construction of non-covalent single-chain Fv dimers for hepatocellular carcinoma and their biological functions.
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World J Hepatol,
2,
185-191.
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S.Hirota,
Y.Hattori,
S.Nagao,
M.Taketa,
H.Komori,
H.Kamikubo,
Z.Wang,
I.Takahashi,
S.Negi,
Y.Sugiura,
M.Kataoka,
and
Y.Higuchi
(2010).
Cytochrome c polymerization by successive domain swapping at the C-terminal helix.
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Proc Natl Acad Sci U S A,
107,
12854-12859.
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PDB codes:
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C.N.Falco,
K.M.Dykstra,
B.P.Yates,
and
P.B.Berget
(2009).
scFv-based fluorogen activating proteins and variable domain inhibitors as fluorescent biosensor platforms.
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Biotechnol J,
4,
1328-1336.
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D.Kuroda,
H.Shirai,
M.Kobori,
and
H.Nakamura
(2009).
Systematic classification of CDR-L3 in antibodies: implications of the light chain subtypes and the VL-VH interface.
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Proteins,
75,
139-146.
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L.A.Clark,
P.A.Boriack-Sjodin,
E.Day,
J.Eldredge,
C.Fitch,
M.Jarpe,
S.Miller,
Y.Li,
K.Simon,
and
H.W.van Vlijmen
(2009).
An antibody loop replacement design feasibility study and a loop-swapped dimer structure.
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Protein Eng Des Sel,
22,
93.
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PDB code:
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D.Kuroda,
H.Shirai,
M.Kobori,
and
H.Nakamura
(2008).
Structural classification of CDR-H3 revisited: a lesson in antibody modeling.
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Proteins,
73,
608-620.
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P.Holliger,
and
P.J.Hudson
(2005).
Engineered antibody fragments and the rise of single domains.
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Nat Biotechnol,
23,
1126-1136.
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M.H.Ali,
E.Peisach,
K.N.Allen,
and
B.Imperiali
(2004).
X-ray structure analysis of a designed oligomeric miniprotein reveals a discrete quaternary architecture.
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Proc Natl Acad Sci U S A,
101,
12183-12188.
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PDB codes:
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B.E.Power,
L.Doughty,
D.R.Shapira,
J.E.Burns,
A.M.Bayly,
J.M.Caine,
Z.Liu,
A.M.Scott,
P.J.Hudson,
and
A.A.Kortt
(2003).
Noncovalent scFv multimers of tumor-targeting anti-Lewis(y) hu3S193 humanized antibody.
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Protein Sci,
12,
734-747.
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Y.Liu,
and
D.Eisenberg
(2002).
3D domain swapping: as domains continue to swap.
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Protein Sci,
11,
1285-1299.
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N.L.Ogihara,
G.Ghirlanda,
J.W.Bryson,
M.Gingery,
W.F.DeGrado,
and
D.Eisenberg
(2001).
Design of three-dimensional domain-swapped dimers and fibrous oligomers.
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Proc Natl Acad Sci U S A,
98,
1404-1409.
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PDB code:
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J.Maynard,
and
G.Georgiou
(2000).
Antibody engineering.
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Annu Rev Biomed Eng,
2,
339-376.
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S.P.Martsev,
A.A.Chumanevich,
A.P.Vlasov,
A.P.Dubnovitsky,
Y.I.Tsybovsky,
S.M.Deyev,
A.Cozzi,
P.Arosio,
and
Z.I.Kravchuk
(2000).
Antiferritin single-chain Fv fragment is a functional protein with properties of a partially structured state: comparison with the completely folded V(L) domain.
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Biochemistry,
39,
8047-8057.
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I.Zegers,
J.Deswarte,
and
L.Wyns
(1999).
Trimeric domain-swapped barnase.
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Proc Natl Acad Sci U S A,
96,
818-822.
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PDB code:
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A.D.Griffiths,
and
A.R.Duncan
(1998).
Strategies for selection of antibodies by phage display.
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Curr Opin Biotechnol,
9,
102-108.
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K.M.Arndt,
K.M.Müller,
and
A.Plückthun
(1998).
Factors influencing the dimer to monomer transition of an antibody single-chain Fv fragment.
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Biochemistry,
37,
12918-12926.
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P.J.Hudson
(1998).
Recombinant antibody fragments.
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Curr Opin Biotechnol,
9,
395-402.
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W.Dall'Acqua,
and
P.Carter
(1998).
Antibody engineering.
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Curr Opin Struct Biol,
8,
443-450.
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Y.Liu,
P.J.Hart,
M.P.Schlunegger,
and
D.Eisenberg
(1998).
The crystal structure of a 3D domain-swapped dimer of RNase A at a 2.1-A resolution.
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Proc Natl Acad Sci U S A,
95,
3437-3442.
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PDB code:
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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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Links
