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PDBsum entry 2bjm
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Immune system
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PDB id
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2bjm
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References listed in PDB file
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Key reference
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Title
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Structure and kinetics of a transient antibody binding intermediate reveal a kinetic discrimination mechanism in antigen recognition.
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Authors
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L.C.James,
D.S.Tawfik.
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Ref.
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Proc Natl Acad Sci U S A, 2005,
102,
12730-12735.
[DOI no: ]
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PubMed id
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Abstract
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Induced fit is a predominant phenomenon in protein-ligand interactions, yet it
is invariably attributed without establishing the existence, let alone the
structure, of the initial, low-affinity encounter complex. We determined the
crystal structure of the encounter complex on the pathway of ligand binding by
IgE antibody SPE7. We show that this complex is formed by a wide range of
ligands that initially bind with identical affinity. Nonspecific ligands rapidly
dissociate, whereupon the antibody isomerizes to a nonbinding isomer. Specific
ligand complexes, however, slowly isomerize to give a high-affinity complex.
This isomerization involves backbone and side-chain rearrangements of up to 14 A
and the formation of specific hydrogen bonds. The postbinding conformational
switch, combined with the prebinding isomerization to an energetically favorable
nonbinding isomer, results in a "kinetic discrimination" mechanism
that mediates selective binding, by a factor of >10(3), between highly related
ligands that initially bind with the same affinity. This model may apply to
proteins that bind multiple ligands in a specific manner or other proteins that,
although capable of binding many ligands, are activated by only a few.
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Figure 3.
Fig. 3. The binding-site conformations of SPE7. The
semitransparent surface view is colored by electrostatic
potential (blue for positive, red for negative). Noted are
light-chain (L) and heavy-chain (H) CDR3 loops and residues that
play a key role in ligand binding. The free antibody isomer Ab^2
1OCW (7) forms a nonspecific encounter complex with a range of
ligands, as can be seen in the Ab^2·anthrone structure
1BJM. The latter isomerizes to give the final, high-affinity
complex Ab^3·alizarin red 1OAR (see also Movie 3). The
ligands stacks against L3 residue Trp-93 in both the Ab^2 and
Ab^3 complexes, but anthrone makes no hydrogen bonds with Ab^2.
In contrast, alizarin red makes a number of hydrogen bonds to
Ab^3.
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Figure 4.
Fig. 4. Superposition of H3 loops at different stages of
ligand complexation. Shown are CDR loops and side chains for
Ab^2 (gray), Ab^2·anthrone (green), and
Ab^3·alizarin red (yellow). Although the Ab^2 and
Ab^2·anthrone structures vary only slightly (Movie 1),
the formation of the final high-affinity complex
(Ab^3·alizarin red) is accompanied by significant
conformational change, in particular of the H3 loop (Movie 3).
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