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* Residue conservation analysis
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Enzyme class:
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Chain B:
E.C.2.7.11.30
- Receptor protein serine/threonine kinase.
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Reaction:
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ATP + [receptor-protein] = ADP + [receptor-protein] phosphate
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ATP
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[receptor-protein]
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ADP
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[receptor-protein] phosphate
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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Gene Ontology (GO) functional annotation
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Cellular component
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membrane
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1 term
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Biological process
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protein amino acid phosphorylation
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1 term
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Biochemical function
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growth factor activity
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4 terms
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DOI no:
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Nat Struct Biol
9:203-208
(2002)
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PubMed id:
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Crystal structure of the human TbetaR2 ectodomain--TGF-beta3 complex.
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P.J.Hart,
S.Deep,
A.B.Taylor,
Z.Shu,
C.S.Hinck,
A.P.Hinck.
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ABSTRACT
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Transforming growth factor-beta (TGF-beta) is the prototype of a large family of
structurally related cytokines that play key roles in maintaining cellular
homeostasis by signaling through two classes of functionally distinct Ser/Thr
kinase receptors, designated as type I and type II. TGF-beta initiates receptor
assembly by binding with high affinity to the type II receptor. Here, we present
the 2.15 A crystal structure of the extracellular ligand-binding domain of the
human TGF-beta type II receptor (ecTbetaR2) in complex with human TGF-beta3.
ecTbetaR2 interacts with homodimeric TGF-beta3 by binding identical finger
segments at opposite ends of the growth factor. Relative to the canonical
'closed' conformation previously observed in ligand structures across the
superfamily, ecTbetaR2-bound TGF-beta3 shows an altered arrangement of its
monomeric subunits, designated the 'open' conformation. The mode of TGF-beta3
binding shown by ecTbetaR2 is compatible with both ligand conformations. This,
in addition to the predicted mode for TGF-beta binding to the type I receptor
ectodomain (ecTbetaR1), suggests an assembly mechanism in which ecTbetaR1 and
ecTbetaR2 bind at adjacent positions on the ligand surface and directly contact
each other via protein--protein interactions.
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Selected figure(s)
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Figure 1.
Figure 1. Structure of the (ecT R2)[2]−TGF-
3
complex. a, Side view of the complex, with two ecT R2
molecules (green) and the two TGF- 3
monomers (blue and red). The TGF- 3
interchain disulfide bond is shown in black. The major secondary
structural elements, as determined by the DSSP algorithm^42, and
chain termini are labeled. b, Stereo view of ecT R2
(green) superimposed with ecActR2 (pink). The four ecT R2
disulfide bonds structurally equivalent to those in ecActR2 —
28-61, 54-78, 98-113 and 115-120 — are shown in blue. The two
disulfides present within ecT R2
loop 1 (L1), 31-48 and 38-44, but not in ecActR2 are shown in
red. The one disulfide present within ecActR2, 66-85, but not
ecT R2
is shown in black. Side chains of the three ecT R2
residues at the interface with TGF- 3,
Leu 27, Ile 53 and Glu 119, are shown in black. 4
designates -strand
4 that binds in the cleft between the TGF- 3
fingertips. ecActR2 residues that comprise the putative
interface with activin, Phe 42, Trp 60 and Phe 83, are shown in
red. ecT R2
loop 4 (L4) packs against the surface of the central -sheet,
decreasing the accessibility of ecT R2
residues structurally equivalent to ecActR2 Phe 42, Trp 60 and
Phe 83. c, Structural differences between bound and free TGF-
3.
ecT R2-bound
(blue and red monomers) and free (magenta and tan monomers) TGF-
3
homodimer structures are depicted by the left and right images,
respectively. Shown within a single monomer are the 'fingertips'
and the BMP type IA and putative type II receptor binding
epitopes, designated as the 'wrist' and 'knuckle', respectively.
For clarity, the 'thumb' epitope is shown on the
symmetry-related monomer. d, Comparison of the free and bound
TGF- 3
homodimer structures, in which the structures have been aligned
by maximizing the alignment between the blue monomer of the
bound form and the magenta monomer of the free form (1.1 Å
root mean square (r.m.s.) deviation). Relative to the second
monomer of free TGF- 3
(tan), the second monomer of the ecT R2-bound
form (red) is rotated 101° around the axis shown.
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Figure 3.
Figure 3. Contacts at the (ecT R2)[2]−TGF-
3
interface. a, Stereo view of the ecT R2−TGF-
3
interface in which the backbone and side chains of ecT R2
and TGF- 3
are green and blue, respectively. Disulfide bonds are black.
Amino acid side chains are labeled according to the their
residue numbers. b, Stereo view of the hydrogen-bonded ion pair
between ecT R2
Asp 32 and TGF- 3
Arg 94. ecT R2
backbone and side chains are depicted in green; TGF- 3,
in blue; and the interfacial water molecules, by red spheres.
The [A]-weighted^44
electron density, with coefficients 2mF[o] - DF[c], is contoured
at 1.1 .
c, The molecular interaction surfaces of ecT R2
(top) and TGF- 3
(bottom). The molecules are color coded according to the
electrostatic potential and are contoured at 25
kT. The interaction surfaces are defined by pairs of charged
amino acids that lie at the periphery of their binding sites:
Glu 119 and Asp 32 in ecT R2,
and Arg 25 and Arg 94 in TGF- 3.
In the complex, ecT R2
Asp 32 pairs with TGF- 3
Arg 94, and ecT R2
Glu 119 pairs with TGF- 3
Arg 25, as indicated by the arrows.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Struct Biol
(2002,
9,
203-208)
copyright 2002.
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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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EMBO J, 30,
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EMBO J, 28,
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PDB code:
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PDB code:
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PDB codes:
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PDB code:
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S.N.Albright,
and
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PDB code:
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Structure, 14,
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PDB codes:
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D.P.Philips,
W.L.Miller,
and
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and
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Crystal structure of the human urokinase plasminogen activator receptor bound to an antagonist peptide.
|
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EMBO J, 24,
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PDB code:
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T.B.Thompson,
S.P.Kurup,
T.S.Jardetzky,
and
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J Biol Chem, 279,
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(2004).
Molecular recognition of BMP-2 and BMP receptor IA.
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Nat Struct Mol Biol, 11,
481-488.
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PDB codes:
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V.M.Leppänen,
M.M.Bespalov,
P.Runeberg-Roos,
U.Puurand,
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and
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The structure of GFRalpha1 domain 3 reveals new insights into GDNF binding and RET activation.
|
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EMBO J, 23,
1452-1462.
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PDB code:
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W.Sebald,
J.Nickel,
J.L.Zhang,
and
T.D.Mueller
(2004).
Molecular recognition in bone morphogenetic protein (BMP)/receptor interaction.
|
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Biol Chem, 385,
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D.G.Winkler,
M.K.Sutherland,
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T.Hayes,
J.E.Skonier,
D.Shpektor,
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B.R.Kovacevich,
K.Staehling-Hampton,
M.Appleby,
M.E.Brunkow,
and
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(2003).
Osteocyte control of bone formation via sclerostin, a novel BMP antagonist.
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EMBO J, 22,
6267-6276.
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J.Greenwald,
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P.Gray,
E.Wiater,
W.Kwiatkowski,
W.Vale,
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S.Choe
(2003).
The BMP7/ActRII extracellular domain complex provides new insights into the cooperative nature of receptor assembly.
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Mol Cell, 11,
605-617.
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PDB codes:
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K.Miyazono,
H.Suzuki,
and
T.Imamura
(2003).
Regulation of TGF-beta signaling and its roles in progression of tumors.
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Cancer Sci, 94,
230-234.
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T.B.Thompson,
T.K.Woodruff,
and
T.S.Jardetzky
(2003).
Structures of an ActRIIB:activin A complex reveal a novel binding mode for TGF-beta ligand:receptor interactions.
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EMBO J, 22,
1555-1566.
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PDB codes:
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W.Sebald,
and
T.D.Mueller
(2003).
The interaction of BMP-7 and ActRII implicates a new mode of receptor assembly.
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Smad3 allostery links TGF-beta receptor kinase activation to transcriptional control.
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Genes Dev, 16,
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PDB codes:
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C.C.Boesen,
S.Radaev,
S.A.Motyka,
A.Patamawenu,
and
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The 1.1 A crystal structure of human TGF-beta type II receptor ligand binding domain.
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Structure, 10,
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PDB code:
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E.V.Bocharov,
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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
code is
shown on the right.
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