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* Residue conservation analysis
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Enzyme class:
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Chains L, M:
E.C.3.2.1.17
- lysozyme.
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Reaction:
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Hydrolysis of the 1,4-beta-linkages between N-acetyl-D-glucosamine and N-acetylmuramic acid in peptidoglycan heteropolymers of the prokaryotes cell walls.
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DOI no:
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J Mol Biol
367:358-372
(2007)
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PubMed id:
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Maturation of shark single-domain (IgNAR) antibodies: evidence for induced-fit binding.
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R.L.Stanfield,
H.Dooley,
P.Verdino,
M.F.Flajnik,
I.A.Wilson.
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ABSTRACT
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Sharks express an unusual heavy-chain isotype called IgNAR, whose variable
regions bind antigen as independent soluble domains. To further probe affinity
maturation of the IgNAR response, we structurally characterized the germline and
somatically matured versions of a type II variable (V) region, both in the
presence and absence of its antigen, hen egg-white lysozyme. Despite a disulfide
bond linking complementarity determining regions (CDRs) 1 and 3, both germline
and somatically matured V regions displayed significant structural changes in
these CDRs upon complex formation with antigen. Somatic mutations in the IgNAR V
region serve to increase the number of contacts with antigen, as reflected by a
tenfold increase in affinity, and one of these mutations appears to stabilize
the CDR3 region. In addition, a residue in the HV4 loop plays an important role
in antibody-antigen interaction, consistent with the high rate of somatic
mutations in this non-CDR loop.
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Selected figure(s)
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Figure 3.
Figure 3. Different CDR1–CDR3 contacts in Ancestral and
PBLA8. (a) unliganded Ancestral, (b) unliganded PBLA8, (c)
liganded Ancestral, (d) liganded PBLA8. Residue 28 is an Asn in
the Ancestral structure (a) and an Arg in PBLA8 (b). PBLA8 Arg28
forms a salt-bridge with Asp93 that may serve to stabilize
CDR3; this interaction is absent in the Ancestral structure.
The PBLA8 Arg28-Asp93 salt-bridge must be broken to bind
lysozyme (d) where Asp93 forms a salt-bridge with lysozyme
residue ArgL112. Figure 3. Different CDR1–CDR3 contacts in
Ancestral and PBLA8. (a) unliganded Ancestral, (b) unliganded
PBLA8, (c) liganded Ancestral, (d) liganded PBLA8. Residue 28 is
an Asn in the Ancestral structure (a) and an Arg in PBLA8 (b).
PBLA8 Arg28 forms a salt-bridge with Asp93 that may serve to
stabilize CDR3; this interaction is absent in the Ancestral
structure. The PBLA8 Arg28-Asp93 salt-bridge must be broken to
bind lysozyme (d) where Asp93 forms a salt-bridge with lysozyme
residue ArgL112.
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Figure 7.
Figure 7. Comparison of IgNAR V domain and human NEW Vλ
domain. The NEW Vλ domain has an unusual deletion of the CDR2
region, similar to that seen in the IgNAR V domains. Figure
7. Comparison of IgNAR V domain and human NEW Vλ domain. The
NEW Vλ domain has an unusual deletion of the CDR2 region,
similar to that seen in the IgNAR V domains.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2007,
367,
358-372)
copyright 2007.
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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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L.Deng,
C.A.Velikovsky,
G.Xu,
L.M.Iyer,
S.Tasumi,
M.C.Kerzic,
M.F.Flajnik,
L.Aravind,
Z.Pancer,
and
R.A.Mariuzza
(2010).
A structural basis for antigen recognition by the T cell-like lymphocytes of sea lamprey.
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Proc Natl Acad Sci U S A,
107,
13408-13413.
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PDB codes:
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R.A.Mariuzza,
C.A.Velikovsky,
L.Deng,
G.Xu,
and
Z.Pancer
(2010).
Structural insights into the evolution of the adaptive immune system: the variable lymphocyte receptors of jawless vertebrates.
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Biol Chem,
391,
753-760.
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A.Monegal,
D.Ami,
C.Martinelli,
H.Huang,
M.Aliprandi,
P.Capasso,
C.Francavilla,
G.Ossolengo,
and
A.de Marco
(2009).
Immunological applications of single-domain llama recombinant antibodies isolated from a naïve library.
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Protein Eng Des Sel,
22,
273-280.
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C.A.Velikovsky,
L.Deng,
S.Tasumi,
L.M.Iyer,
M.C.Kerzic,
L.Aravind,
Z.Pancer,
and
R.A.Mariuzza
(2009).
Structure of a lamprey variable lymphocyte receptor in complex with a protein antigen.
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Nat Struct Mol Biol,
16,
725-730.
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PDB codes:
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L.Bloom,
and
V.Calabro
(2009).
FN3: a new protein scaffold reaches the clinic.
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Drug Discov Today,
14,
949-955.
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M.Arbabi-Ghahroudi,
R.To,
N.Gaudette,
T.Hirama,
W.Ding,
R.MacKenzie,
and
J.Tanha
(2009).
Aggregation-resistant VHs selected by in vitro evolution tend to have disulfide-bonded loops and acidic isoelectric points.
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Protein Eng Des Sel,
22,
59-66.
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D.P.Simmons,
V.A.Streltsov,
O.Dolezal,
P.J.Hudson,
A.M.Coley,
M.Foley,
D.F.Proll,
and
S.D.Nuttall
(2008).
Shark IgNAR antibody mimotopes target a murine immunoglobulin through extended CDR3 loop structures.
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Proteins,
71,
119-130.
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PDB codes:
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J.L.Liu,
G.P.Anderson,
and
E.R.Goldman
(2007).
Isolation of anti-toxin single domain antibodies from a semi-synthetic spiny dogfish shark display library.
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BMC Biotechnol,
7,
78.
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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
