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PDBsum entry 1jgv
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Immune system
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PDB id
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1jgv
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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 a disfavored elimination reaction in catalytic antibody 1d4.
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Authors
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N.A.Larsen,
A.Heine,
L.Crane,
B.F.Cravatt,
R.A.Lerner,
I.A.Wilson.
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Ref.
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J Mol Biol, 2001,
314,
93.
[DOI no: ]
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PubMed id
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Abstract
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Murine antibody 1D4 selectively catalyzes a highly disfavored beta-elimination
reaction. Crystal structures of unliganded 1D4 and 1D4 in complex with a
transition-state analog (TSA) have elucidated a possible general base mode of
catalysis. The structures of the unliganded and liganded Fabs were determined to
1.80 and 1.85 A resolution, respectively. The structure of the complex reveals a
binding pocket with high shape complementarity to the TSA, which is recruited to
coerce the substrate into the sterically demanding, eclipsed conformation that
is required for catalysis. A histidine residue and two water molecules are
likely involved in the catalysis. The structure supports either a concerted E2
or stepwise E1cB-like mechanism for elimination. Finally, the liganded 1D4
structure shows minor conformational rearrangements in CDR H2, indicative of
induced-fit binding of the hapten. 1D4 has pushed the boundaries of
antibody-mediated catalysis into the realm of disfavored reactions and, hence,
represents an important milestone in the development of this technology.
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Figure 3.
Figure 3. Stereo representations of the hapten interactions
in the antigen-binding pocket. (a) Hydrogen bonds are shown as
broken green lines. Arg^H100 forms an apparent cation-π
sandwich with Tyr^L32 and the phenyl ring in the hapten[21], and
prevents further interactions of the hapten with CDR L1 or L2.
(b) The side view of the binding pocket shows that the majority
of the side-chain interactions are derived from the heavy chain.
His^H58 stacks against the second phenyl ring in the substrate.
Leu^L96 has been omitted from this view for clarity.
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Figure 6.
Figure 6. Substrate modeling by superposition on the
hapten. Most of the antibody interactions with the hapten and
substrate alike are directed towards the two phenyl rings. The
putative hydroxide ion is positioned to abstract the hydrogen
atom from the substrate, while the water molecule forms a
hydrogen bond with the substrate carbonyl group, possibly
lowering the p K[a] of the abstracted proton.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2001,
314,
93-0)
copyright 2001.
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