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PDBsum entry 1lkk
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Complex (tyrosine kinase/peptide)
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PDB id
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1lkk
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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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Crystal structures of the human p56lck sh2 domain in complex with two short phosphotyrosyl peptides at 1.0 a and 1.8 a resolution.
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Authors
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L.Tong,
T.C.Warren,
J.King,
R.Betageri,
J.Rose,
S.Jakes.
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Ref.
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J Mol Biol, 1996,
256,
601-610.
[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
93%.
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Abstract
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src homology 2 (SH2) domains are modules of about 100 amino acid residues and
bind to phosphotyrosine-containing motifs in a sequence-specific manner. They
play important roles in intracellular signal transduction and represent
potential targets for pharmacological intervention. The protein tyrosine kinase
p56lck is a member of the src family and is involved in T-cell activation. The
crystal structure of its SH2 domain with an 11-residue peptide showed that the
phosphotyrosine and the Ile residue at the pY + 3 position are recognized by the
SH2 domain. We present here the crystal structure of the SH2 domain of human
p56lck in complex with the short phosphotyrosyl peptide Ac-pTyr-Glu-Glu-Ile
(pYEEI peptide) at 1.0 A resolution. The structural analysis at atomic
resolution reveals that residue Arg134 (alphaA2), which interacts with the
phosphotyrosine side-chain, is present in two conformations in the complex. The
structure at 1.8 A resolution of the complex with the phosphotyrosyl peptide
Ac-pTyr-Glu-Glu-Gly (pYEEG peptide), which is 11 fold less potent, shows another
binding mode for the pY + 3 residue as well as rearrangements of the side-chain
of Arg196 (EF3) and one of the water molecules at the base of the pY + 3 pocket.
The structure of the complex with the short pYEEI peptide at atomic resolution
represents a good starting point for the design and optimization of new
inhibitors. Comparative structural analysis of many different inhibitor
complexes will be an important component of this drug discovery process.
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Figure 6.
Figure 6. The environment of the phosphotyrosine side-chain in the pYEEI complex. The phosphate group is involved
in an intricate network of hydrogen-bonding and charge--charge interactions (thin green lines) with residues in the SH2
domain (thin black lines) and water molecules (red dots). The three terminal oxygen atoms are numbered. The aromatic
ring of the phosphotyrosine is situated between the aliphatic portion of Lys182 (bD6) and the guanidinium group of
Arg134 (aA2).
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Figure 8.
Figure 8. Superposition of the bound conformations of
the pYEEI (thin lines) and the pYEEG (thick lines)
peptides.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(1996,
256,
601-610)
copyright 1996.
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