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PDBsum entry 2c1p
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Immune system
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PDB id
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2c1p
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References listed in PDB file
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Key reference
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Title
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Crystal structures of an enantioselective FAB-Fragment in free and complex forms.
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Authors
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T.Parkkinen,
T.K.Nevanen,
A.Koivula,
J.Rouvinen.
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Ref.
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J Mol Biol, 2006,
357,
471-480.
[DOI no: ]
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PubMed id
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Note In the PDB file this reference is
annotated as "TO BE PUBLISHED".
The citation details given above were identified by an automated
search of PubMed on title and author
names, giving a
percentage match of
94%.
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Abstract
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Enantioselective antibodies can separate the enantiomers of a chiral compound in
a highly specific manner. We have recently reported the cloning and applications
of a recombinant Fab-fragment, ENA11His, in the enantioseparation of a drug
candidate, finrozole, which contains two chiral centers. Here, the crystal
structures of this enantioselective antibody Fab-fragment are determined in the
absence of the hapten at a resolution of 2.75 A, and in the presence of the
hapten at 2.05 A resolution. The conformation of the protein was found to be
similar in both free and complex forms. The hapten molecule was tightly bound in
a deep cleft between the light and heavy chains of the Fab-fragment. The complex
structure also allowed us to describe the molecular basis for enantioselectivity
and to deduce the absolute configurations of all the four different
stereoisomers (a-d) of finrozole. The ENA11His antibody fragment selectively
binds the SR (a) enantiomer from the racemic mixture of a and d-enantiomers,
thus allowing separation from the pharmacologically most active RS enantiomer
(d). In particular, Asp95 and Asn35 of the H-chain in the ENA11 His antibody
seem to provide this specificity through hydrogen bonding.
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Figure 2.
Figure 2. Comparison of the inhibition effect of the
soluble stereoisomers a, b, c, and d on the binding of ENA11His
to the ad-BSA surface of a BIAcore sensor chip. The a and b
stereoisomers show the strongest inhibition effect by lowering
the binding response the most. DMSO is a control, as described
in the text.
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Figure 4.
Figure 4. A stereo view of the electron density map of the
a-enantiomer in the ENA11His Fab binding site at 2.05 Å
resolution. The F[o] -F[c] omit map is contoured at 3s. The
electron density clearly shows that only the SR configuration is
bound into the binding site.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2006,
357,
471-480)
copyright 2006.
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