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PDBsum entry 2aoa
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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 a high-Affinity macrocyclic peptide mimetic in complex with the grb2 sh2 domain.
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Authors
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J.Phan,
Z.D.Shi,
T.R.Burke,
D.S.Waugh.
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Ref.
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J Mol Biol, 2005,
353,
104-115.
[DOI no: ]
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PubMed id
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Abstract
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The high-affinity binding of the growth factor receptor-bound protein 2 (Grb2)
SH2 domain to tyrosine-phosphorylated cytosolic domains of receptor tyrosine
kinases (RTKs) is an attractive target for therapeutic intervention in many
types of cancer. We report here two crystal forms of a complex between the Grb2
SH2 domain and a potent non-phosphorus-containing macrocyclic peptide mimetic
that exhibits significant anti-proliferative effects against erbB-2-dependent
breast cancers. This agent represents a "second generation" inhibitor
with greatly improved binding affinity and bio-availability compared to its
open-chain counterpart. The structures were determined at 2.0A and 1.8A with one
and two domain-swapped dimers per asymmetric unit, respectively. The mode of
binding and specific interactions between the protein and the inhibitor provide
insight into the high potency of this class of macrocylic compounds and may aid
in further optimization as part of the iterative rational drug design process.
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Figure 3.
Figure 3. Diagrams of the hydrogen bonding networks in the
active site of (a) subunit A and (b) subunit B with the Grb2 SH2
domain represented in cartoon, ligand-binding residues in bonds
with grey carbon atoms, and ligands in ball-and-stick with green
carbon atoms. Hydrogen bonds are in cyan broken lines and
intramolecular bonds in red. Selected atoms of S1s are labeled
in red.
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Figure 4.
Figure 4. (a) Binding interactions between two S1s
molecules and the Grb2 SH2 domain in the C site, green and
orange, and D site, cyan and yellow ball-and-stick models. (b)
Stereo view of the superposition of Grb2 SH2 ligands from PDB
entries 1ZFP (magenta), 1FYR (gold), 1BM2 (cyan), 1TZE (slate
blue), and 1CJ1 (tomato) on subunit A S1s (green). The carbon
atoms of the S1s-binding residues in ball-and-stick are grey and
the ligands are in bonds. Hydrogen bonds are shown in red broken
lines for S1s. Superposition of all 12 S1s molecules in stereo
showing different side-chain rotamers and conformational changes
derived from binding in the various pockets of the
domain-swapped dimer. (c) Those that bound in the A site are in
black, B site in dark green, C site in orange and red, and D
site in blue and cyan.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2005,
353,
104-115)
copyright 2005.
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