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* Residue conservation analysis
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Enzyme class:
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Chains B, D:
E.C.2.7.10.1
- receptor protein-tyrosine kinase.
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Reaction:
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L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H+
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L-tyrosyl-[protein]
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+
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ATP
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=
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O-phospho-L-tyrosyl-[protein]
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+
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ADP
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Structure
16:460-467
(2008)
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PubMed id:
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Mechanism of activation and inhibition of the HER4/ErbB4 kinase.
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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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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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Selected figure(s)
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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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Figures were
selected
by an automated process.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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N.Jura,
X.Zhang,
N.F.Endres,
M.A.Seeliger,
T.Schindler,
and
J.Kuriyan
(2011).
Catalytic control in the EGF receptor and its connection to general kinase regulatory mechanisms.
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Mol Cell,
42,
9.
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A.Bill,
A.Schmitz,
B.Albertoni,
J.N.Song,
L.C.Heukamp,
D.Walrafen,
F.Thorwirth,
P.J.Verveer,
S.Zimmer,
L.Meffert,
A.Schreiber,
S.Chatterjee,
R.K.Thomas,
R.T.Ullrich,
T.Lang,
and
M.Famulok
(2010).
Cytohesins are cytoplasmic ErbB receptor activators.
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Cell,
143,
201-211.
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C.S.Gerbin,
and
R.Landgraf
(2010).
Geldanamycin selectively targets the nascent form of ERBB3 for degradation.
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Cell Stress Chaperones,
15,
529-544.
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D.Alvarado,
D.E.Klein,
and
M.A.Lemmon
(2010).
Structural basis for negative cooperativity in growth factor binding to an EGF receptor.
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Cell,
142,
568-579.
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PDB codes:
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D.N.Amin,
N.Sergina,
D.Ahuja,
M.McMahon,
J.A.Blair,
D.Wang,
B.Hann,
K.M.Koch,
K.M.Shokat,
and
M.M.Moasser
(2010).
Resiliency and vulnerability in the HER2-HER3 tumorigenic driver.
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Sci Transl Med,
2,
16ra7.
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F.Shi,
S.E.Telesco,
Y.Liu,
R.Radhakrishnan,
and
M.A.Lemmon
(2010).
ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation.
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Proc Natl Acad Sci U S A,
107,
7692-7697.
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PDB code:
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J.Monsey,
W.Shen,
P.Schlesinger,
and
R.Bose
(2010).
Her4 and Her2/neu tyrosine kinase domains dimerize and activate in a reconstituted in vitro system.
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J Biol Chem,
285,
7035-7044.
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W.W.Li,
J.J.Chen,
R.L.Zheng,
W.Q.Zhang,
Z.X.Cao,
L.L.Yang,
X.Y.Qing,
L.X.Zhou,
L.Yang,
L.D.Yu,
L.J.Chen,
Y.Q.Wei,
and
S.Y.Yang
(2010).
Taking quinazoline as a general support-Nog to design potent and selective kinase inhibitors: application to FMS-like tyrosine kinase 3.
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ChemMedChem,
5,
513-516.
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Z.Zhang,
A.L.Stiegler,
T.J.Boggon,
S.Kobayashi,
and
B.Halmos
(2010).
EGFR-mutated lung cancer: a paradigm of molecular oncology.
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Oncotarget,
1,
497-514.
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C.Qiu,
M.K.Tarrant,
T.Boronina,
P.A.Longo,
J.M.Kavran,
R.N.Cole,
P.A.Cole,
and
D.J.Leahy
(2009).
In vitro enzymatic characterization of near full length EGFR in activated and inhibited states.
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Biochemistry,
48,
6624-6632.
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D.Tvorogov,
M.Sundvall,
K.Kurppa,
M.Hollmén,
S.Repo,
M.S.Johnson,
and
K.Elenius
(2009).
Somatic mutations of ErbB4: selective loss-of-function phenotype affecting signal transduction pathways in cancer.
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J Biol Chem,
284,
5582-5591.
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K.E.Muratore,
M.A.Seeliger,
Z.Wang,
D.Fomina,
J.Neiswinger,
J.J.Havranek,
D.Baker,
J.Kuriyan,
and
P.A.Cole
(2009).
Comparative analysis of mutant tyrosine kinase chemical rescue.
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Biochemistry,
48,
3378-3386.
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PDB code:
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M.A.Lemmon
(2009).
Ligand-induced ErbB receptor dimerization.
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Exp Cell Res,
315,
638-648.
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M.Bennett
(2009).
Positive and negative symptoms in schizophrenia: the NMDA receptor hypofunction hypothesis, neuregulin/ErbB4 and synapse regression.
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Aust N Z J Psychiatry,
43,
711-721.
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M.Red Brewer,
S.H.Choi,
D.Alvarado,
K.Moravcevic,
A.Pozzi,
M.A.Lemmon,
and
G.Carpenter
(2009).
The juxtamembrane region of the EGF receptor functions as an activation domain.
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Mol Cell,
34,
641-651.
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PDB code:
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N.Jura,
N.F.Endres,
K.Engel,
S.Deindl,
R.Das,
M.H.Lamers,
D.E.Wemmer,
X.Zhang,
and
J.Kuriyan
(2009).
Mechanism for activation of the EGF receptor catalytic domain by the juxtamembrane segment.
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Cell,
137,
1293-1307.
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PDB code:
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N.Jura,
Y.Shan,
X.Cao,
D.E.Shaw,
and
J.Kuriyan
(2009).
Structural analysis of the catalytically inactive kinase domain of the human EGF receptor 3.
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Proc Natl Acad Sci U S A,
106,
21608-21613.
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PDB code:
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P.Sengupta,
E.Bosis,
E.Nachliel,
M.Gutman,
S.O.Smith,
G.Mihályné,
I.Zaitseva,
and
S.McLaughlin
(2009).
EGFR juxtamembrane domain, membranes, and calmodulin: kinetics of their interaction.
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Biophys J,
96,
4887-4895.
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R.Bose,
and
X.Zhang
(2009).
The ErbB kinase domain: structural perspectives into kinase activation and inhibition.
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Exp Cell Res,
315,
649-658.
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S.E.Telesco,
and
R.Radhakrishnan
(2009).
Atomistic insights into regulatory mechanisms of the HER2 tyrosine kinase domain: a molecular dynamics study.
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Biophys J,
96,
2321-2334.
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S.Morgan,
and
J.R.Grandis
(2009).
ErbB receptors in the biology and pathology of the aerodigestive tract.
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Exp Cell Res,
315,
572-582.
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T.D.Prickett,
N.S.Agrawal,
X.Wei,
K.E.Yates,
J.C.Lin,
J.R.Wunderlich,
J.C.Cronin,
P.Cruz,
S.A.Rosenberg,
and
Y.Samuels
(2009).
Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4.
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Nat Genet,
41,
1127-1132.
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A.J.Shih,
J.Purvis,
and
R.Radhakrishnan
(2008).
Molecular systems biology of ErbB1 signaling: bridging the gap through multiscale modeling and high-performance computing.
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Mol Biosyst,
4,
1151-1159.
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D.F.Stern
(2008).
ERBB3/HER3 and ERBB2/HER2 duet in mammary development and breast cancer.
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J Mammary Gland Biol Neoplasia,
13,
215-223.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
codes are
shown on the right.
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Links
