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PDBsum entry 25c8
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Catalytic antibody
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PDB id
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25c8
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Structural basis for antibody catalysis of a disfavored ring closure reaction.
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Authors
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K.Gruber,
B.Zhou,
K.N.Houk,
R.A.Lerner,
C.G.Shevlin,
I.A.Wilson.
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Ref.
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Biochemistry, 1999,
38,
7062-7074.
[DOI no: ]
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PubMed id
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Abstract
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The catalysis of disfavored chemical reactions, especially those with no known
natural enzyme counterparts, is one of the most promising achievements of
catalytic antibody research. Antibodies 5C8, 14B9, 17F6, and 26D9, elicited by
two different transition-state analogues, catalyze disfavored endo-tet
cyclization reactions of trans-epoxy alcohols, in formal violation of Baldwin's
rules for ring closure. Thus far, neither chemical nor enzyme catalysis has been
capable of emulating the extraordinary activity and specificity of these
antibodies. X-ray structures of two complexes of Fab 5C8 with the original
hapten and with an inhibitor have been determined to 2.0 A resolution. The Fab
structure has an active site that contains a putative catalytic diad, consisting
of AspH95 and HisL89, capable of general acid/base catalysis. The stabilization
of a positive charge that develops along the reaction coordinate appears to be
an important factor for rate enhancement and for directing the reaction along
the otherwise disfavored pathway. Sequence analysis of the four catalytic
antibodies, as well as four inactive antibodies that strongly bind the
transition-state analogues, suggests a conserved catalytic mechanism. The
occurrence of the putative base HisL89 in all active antibodies, its absence in
three out of the four analyzed inactive antibodies, and the rarity of a
histidine at this position in immunoglobulins support an important catalytic
role for this residue.
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Secondary reference #1
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Title
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Ligand-Induced conformational changes in a catalytic antibody: comparison of the bound and unbound structure of FAB 5c8
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Authors
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K.Gruber,
A.Heine,
E.A.Stura,
C.G.Shevlin,
I.A.Wilson.
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Ref.
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TO BE PUBLISHED ...
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