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PDBsum entry 1ncw
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Immune system
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PDB id
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1ncw
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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 cationic cyclization reaction.
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Authors
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X.Zhu,
A.Heine,
F.Monnat,
K.N.Houk,
K.D.Janda,
I.A.Wilson.
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Ref.
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J Mol Biol, 2003,
329,
69-83.
[DOI no: ]
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PubMed id
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Abstract
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Antibody 4C6 efficiently catalyzes a cationic cyclization reaction. Crystal
structures of the antibody 4C6 Fab in complex with benzoic acid and in complex
with its eliciting hapten were determined to 1.30A and 2.45A resolution,
respectively. These crystal structures, together with computational analysis,
have elucidated a possible mechanism for the monocyclization reaction. The
hapten complex revealed a combining site pocket with high shape complementarity
to the hapten. This active site cleft is dominated by aromatic residues that
shield the highly reactive carbocation intermediates from solvent and stabilize
the carbocation intermediates through cation-pi interactions. Modeling of an
acyclic olefinic sulfonate ester substrate and the transition state (TS)
structures shows that the chair-like transition state is favored, and trapping
by water directly produces trans-2-(dimethylphenylsilyl)-cyclohexanol, whereas
the less favored boat-like transition state leads to cyclohexene. The only
significant change observed upon hapten binding is a side-chain rotation of
Trp(L89), which reorients to form the base of the combining site. Intriguingly,
a benzoic acid molecule was sequestered in the combining site of the unliganded
antibody. The 4C6 active site was compared to that observed in a previously
reported tandem cyclization antibody 19A4 hapten complex. These cationic
cyclization antibodies exhibit convergent structural features with terpenoid
cyclases that appear to be important for catalysis.
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Figure 3.
Figure 3. Shape complementarity of benzoic acid (a) and
hapten (b) in the antibody 4C6 combining site. The Fab
4C6-binding pockets are shown with the molecular surfaces (1.4
Å probe radius). The shape of active sites differs
dramatically between two structures primarily due to the
side-chain of TrpL89, which flips downward to form the base of
the hapten-binding pocket by the rotation of the x[2] angle
about 65° on hapten binding. For further information, see
the text and Figure 4. The Figure was generated in GRASP. [59.]
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Figure 9.
Figure 9. Docking of reactants (13, 15, 17) and TS
structures (14, 16, 18) into the hapten-binding site of the 4C6
Fab structure. (a) Pathway yielding of (1S),(2S)-product,
E[docked] (13)= -14.1 kcal/mol, E[docked] (14)= -10.6 kcal/mol.
(b) Pathway yielding of the (1R),(2R)-enantiomeric product with
E[docked] (15)= -14.7 kcal/mol and E[docked] (16)= -10.9
kcal/mol. (c) Pathway yielding cyclohexene, E[docked] (17)=
-14.6 kcal/mol and E[docked] (18)= -9.2 kcal/mol. The first two
TS, 14 and 16, correspond to both enantiomers of the chair-like
TS, whereas the last one (18) is the boat-like TS.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2003,
329,
69-83)
copyright 2003.
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