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PDBsum entry 3bbw
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References listed in PDB file
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Key reference
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Title
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Mechanism of activation and inhibition of the her4/erbb4 kinase.
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Authors
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C.Qiu,
M.K.Tarrant,
S.H.Choi,
A.Sathyamurthy,
R.Bose,
S.Banjade,
A.Pal,
W.G.Bornmann,
M.A.Lemmon,
P.A.Cole,
D.J.Leahy.
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Ref.
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Structure, 2008,
16,
460-467.
[DOI no: ]
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PubMed id
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Abstract
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HER4/ErbB4 is a ubiquitously expressed member of the EGF/ErbB family of receptor
tyrosine kinases that is essential for normal development of the heart, nervous
system, and mammary gland. We report here crystal structures of the ErbB4 kinase
domain in active and lapatinib-inhibited forms. Active ErbB4 kinase adopts an
asymmetric dimer conformation essentially identical to that observed to be
important for activation of the EGF receptor/ErbB1 kinase. Mutagenesis studies
of intact ErbB4 in Ba/F3 cells confirm the importance of this asymmetric dimer
for activation of intact ErbB4. Lapatinib binds to an inactive form of the ErbB4
kinase in a mode equivalent to its interaction with the EGF receptor. All ErbB4
residues contacted by lapatinib are conserved in the EGF receptor and
HER2/ErbB2, which lapatinib also targets. These results demonstrate that key
elements of kinase activation and inhibition are conserved among ErbB family
members.
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Figure 1.
Figure 1. Ribbon Diagrams of ErbB4 Kinase Structures
(A)
The active conformation of the ErbB4 kinase. The activation loop
is colored red.
(B) An inactive conformation of the ErbB4
kinase in complex with lapatinib, which is shown as a red stick
model. The activation loop is disordered, but the loop termini
are colored red.
(C) Superposition of the active and
inactive conformations of the ErbB4 kinase.
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Figure 2.
Figure 2. Superposition of the Asymmetric Dimers of EGFR and
ErbB4 Kinase
The ErbB4 kinase subunits are colored blue and
cyan. An EGFR dimer is colored light yellow. Only the single
blue colored ErbB4 kinase subunit and corresponding EGFR subunit
were included in the superposition.
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The above figures are
reprinted
by permission from Cell Press:
Structure
(2008,
16,
460-467)
copyright 2008.
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