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PDBsum entry 1bhh
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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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Carboxymethyl-Phenylalanine as a replacement for phosphotyrosine in sh2 domain binding.
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Authors
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L.Tong,
T.C.Warren,
S.Lukas,
J.Schembri-King,
R.Betageri,
J.R.Proudfoot,
S.Jakes.
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Ref.
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J Biol Chem, 1998,
273,
20238-20242.
[DOI no: ]
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PubMed id
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Abstract
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The crystal structure of human p56(lck) SH2 domain in complex with an inhibitor
containing the singly charged p-(carboxymethyl)phenylalanine residue (cmF) as a
phosphotyrosine (Tyr(P) or pY) replacement has been determined at 1.8 A
resolution. The binding mode of the acetyl-cmF-Glu-Glu-Ile (cmFEEI) inhibitor is
very similar to that of the pYEEI inhibitor, confirming that the cmFEEI
inhibitor has a similar mechanism of SH2 domain inhibition despite its
significantly reduced potency. Observed conformational differences in the side
chain of the cmF residue can be interpreted in terms of maintaining similar
interactions with the SH2 domain as the Tyr(P) residue. The crystal structure of
the free p56(lck) SH2 domain has been determined at 1.9 A resolution and shows
an open conformation for the BC loop and an open phosphotyrosine binding pocket,
in contrast to earlier studies on the src SH2 domain that showed mostly closed
conformation. The structural information presented here suggests that the
carboxymethyl-phenylalanine residue may be a viable Tyr(P) replacement and
represents an attractive starting point for the design and development of SH2
domain inhibitors with better pharmaceutical profiles.
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Figure 1.
Fig. 1. The chemical structure of the p56^lck SH2 domain
inhibitor used in the current study. The inhibitor contains a
cmF residue as a replacement for the pY residue. The cmFEEI
inhibitor is about 450-fold less potent than the pYEEI inhibitor
(pH 7.4) in the binding of the SH2 domain.
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Figure 2.
Fig. 2. A, comparison of the overall bound conformations
of the cmFEEI inhibitor (in cyan for carbon atoms) and the pYEEI
inhibitor (in white for carbon atoms). The oxygen atoms are
shown in red, nitrogen is in blue, and phosphorus is in yellow.
Note the remarkable similarity for the Ile residue at the pY+3
position. B, close-up of the conformational overlap of the cmF
and the Tyr(P) residues, showing the translation of the phenyl
ring in the cmF inhibitor. The oxygen atoms on the phosphate
group are numbered. C, same as B, viewed 90 ° away around
the horizontal axis, showing the rotation of the phenyl ring in
the cmF inhibitor.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(1998,
273,
20238-20242)
copyright 1998.
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