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PDBsum entry 2ahx
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Cell cycle,signaling protein
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PDB id
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2ahx
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References listed in PDB file
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Key reference
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Title
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The extracellular region of erbb4 adopts a tethered conformation in the absence of ligand.
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Authors
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S.Bouyain,
P.A.Longo,
S.Li,
K.M.Ferguson,
D.J.Leahy.
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Ref.
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Proc Natl Acad Sci U S A, 2005,
102,
15024-15029.
[DOI no: ]
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PubMed id
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Abstract
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The human ErbB family of receptor tyrosine kinases comprises the epidermal
growth factor receptor (EGFR/ErbB1/HER1), ErbB2 (HER2/Neu), ErbB3 (HER3), and
ErbB4 (HER4). ErbBs play fundamental roles in cell growth and differentiation
events in embryonic and adult tissues, and inappropriate ErbB activity has been
implicated in several human cancers. We report here the 2.4 A crystal structure
of the extracellular region of human ErbB4 in the absence of ligand and show
that it adopts a tethered conformation similar to inactive forms of ErbB1 and
ErbB3. This structure completes the gallery of unliganded ErbB receptors and
demonstrates that all human ligand-binding ErbBs adopt the autoinhibited
conformation. We also show that the binding of neuregulin-1beta to ErbB4 and
ErbB3 and the binding of betacellulin to both ErbB4 and ErbB1 does not decrease
at low pH, unlike the binding of epidermal growth factor and transforming growth
factor-alpha to ErbB1. These results indicate an important role for ligand in
determining pH-dependent binding and may explain different responses observed
when the same ErbB receptor is stimulated by different ligands.
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Figure 2.
Fig. 2. Structure of sErbB4. (A) Ribbon diagram of sErbB4.
Domains I, II, III, and IV are colored blue, green, yellow, and
red, respectively. The N and C termini are indicated by the
letters N and C. (B) Surface representation of sErbB4. The
intramolecular contact between domains II and IV is boxed. (C)
Domain II/IV contact in ligand-binding sErbBs. Residues at the
tether between domains II and IV of sErbB4 are shown in green
(domain II) and red (domain IV). The equivalent residues from
tethered sErbB1 and sErbB3 are shown in gray and white,
respectively (3, 6). The buried surface areas and the surface
complementarity coefficients for each tether are indicated in
the legend.
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Figure 3.
Fig. 3. Comparison of ligand-binding surfaces in sErbB1 and
sErbB4. (A) Conservation of sErbB1 TGF-  -binding residues in
sErbB4. Residues with atoms within4Åofa TGF- residue
are shown in red on surface representations of sErbB1 domains I
and III (4). Residues that are strictly conserved between the
ErbB1 ligand-binding site and ErbB4 are colored blue on surface
representations of sErbB4. (B) Electrostatic potential on the
ligand-binding surfaces of ErbB1 and ErbB4. Regions with
negative electrostatic potential are colored red and regions
with positive electrostatic potential are colored blue (scale
± 10 e/kT).
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