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PDBsum entry 1nql
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Hormone/growth factor receptor
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PDB id
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1nql
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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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Egf activates its receptor by removing interactions that autoinhibit ectodomain dimerization.
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Authors
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K.M.Ferguson,
M.B.Berger,
J.M.Mendrola,
H.S.Cho,
D.J.Leahy,
M.A.Lemmon.
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Ref.
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Mol Cell, 2003,
11,
507-517.
[DOI no: ]
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PubMed id
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Abstract
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Epidermal growth factor (EGF) receptor is the prototype of the ErbB (HER) family
receptor tyrosine kinases (RTKs), which regulate cell growth and differentiation
and are implicated in many human cancers. EGF activates its receptor by inducing
dimerization of the 621 amino acid EGF receptor extracellular region. We
describe the 2.8 A resolution crystal structure of this entire extracellular
region (sEGFR) in an unactivated state. The structure reveals an autoinhibited
configuration, where the dimerization interface recently identified in activated
sEGFR structures is completely occluded by intramolecular interactions. To
activate the receptor, EGF binding must promote a large domain rearrangement
that exposes this dimerization interface. This contrasts starkly with other RTK
activation mechanisms and suggests new approaches for designing ErbB receptor
antagonists.
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Figure 2.
Figure 2. Space-Filling Representation of sEGFR with Domain
I-Bound EGFsEGFR is shown in CPK representation, with subdomains
colored as in Figure 1. Bound EGF is magenta. EGF is intimately
associated with domain I (blue) but does not come closer than 4
Å away from domain III. The side chain of Y14 (projecting
from the left-hand side of EGF) is too distant from domain III
to participate in hydrogen bonding.
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Figure 6.
Figure 6. Different Domain Orientations in Autoinhibited
Structures of sEGFR and sErbB3The structures of autoinhibited
sEGFR and sErbB3 (Cho and Leahy, 2002) were overlaid by
superimposition of domains III and IV.(A) The sEGFR/sErbB3
overlay is shown in the orientation used for sEGFR in Figure 1A.
sEGFR is gray; sErbB3 is magenta.(B) The same sEGFR/sErbB3
overlay is shown in an orthogonal view to illustrate the
different orientation of the domain I/II fragment in the two
structures. The difference is approximated by a 60° rotation
about the axis marked with a black circle.
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The above figures are
reprinted
by permission from Cell Press:
Mol Cell
(2003,
11,
507-517)
copyright 2003.
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