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Contents |
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* Residue conservation analysis
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DOI no:
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Nat Struct Biol
5:993
(1998)
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PubMed id:
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An antagonist peptide-EPO receptor complex suggests that receptor dimerization is not sufficient for activation.
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O.Livnah,
D.L.Johnson,
E.A.Stura,
F.X.Farrell,
F.P.Barbone,
Y.You,
K.D.Liu,
M.A.Goldsmith,
W.He,
C.D.Krause,
S.Pestka,
L.K.Jolliffe,
I.A.Wilson.
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ABSTRACT
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Dimerization of the erythropoietin (EPO) receptor (EPOR), in the presence of
either natural (EPO) or synthetic (EPO-mimetic peptides, EMPs) ligands is the
principal extracellular event that leads to receptor activation. The crystal
structure of the extracellular domain of EPOR bound to an inactive (antagonist)
peptide at 2.7 A resolution has unexpectedly revealed that dimerization still
occurs, but the orientation between receptor molecules is altered relative to
active (agonist) peptide complexes. Comparison of the biological properties of
agonist and antagonist EMPs with EPO suggests that the extracellular domain
orientation is tightly coupled to the cytoplasmic signaling events and, hence,
provides valuable new insights into the design of synthetic ligands for EPOR and
other cytokine receptors.
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Selected figure(s)
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Figure 6.
Figure 6. Stereo representation of the superposition between the
two EMP33 peptides in EBP−EMP33 complex structure. Several
of the side chains are labeled for reference.
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Figure 7.
Figure 7. The hydrophobic interaction surface between EBP and
EMP peptides. a, Comparison between the receptor−peptide
interactions in the EBP−EMP1 (left) and EBP−EMP33 (right)
complexes. In the EBP−EMP1 complex, the receptor and peptides
are colored in blue and cyan and for EBP−EMP33 in magenta and
gold. The Tyr P'4 and DBY P'4 are contributed from the other
peptide partner and, in addition, to their essential role in the
hydrophobic interaction, form the only side chain specific
hydrogen-bond (dotted line) between the peptide and receptor.
The overall architecture of the main hydrophobic interaction
patch, consisting of residues Phe 93, Met 150, and Phe 205 from
the EBP and Phe P8, Trp P13, and Tyr/DBP P'4 from the peptides
remain similar in the two EMP1 and EMP33 structures with the
largest variation being in the actual conformation of the DBY
compared to Tyr 4. b, Stereoview of a 3F[o] - 2F[c] electron
density map calculated at 50−2.7 Šresolution, contoured
at 1.0  (blue)
and 4.5 (red)
with superimposed coordinates from the refined structure. The
orientation for the DBY residue is easily defined by the
positions of the two bromine atoms on the tyrosine ring, as
observed from the high 4.5 level
contour in the electron density map (red). At that cutoff level,
the sulfur from Met 150 is also observed. Phe P8 has been
omitted for clarity.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Struct Biol
(1998,
5,
993-0)
copyright 1998.
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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
|
|
|
|
|
|
M.N.Kostjukova,
and
N.N.Tupitsyn
(2011).
Functional Properties of Extracellular Domains of Transducer Receptor gp130.
|
| |
Biochemistry (Mosc),
76,
394-406.
|
|
|
|
|
|
|
S.Abe,
R.Sasaki,
and
S.Masuda
(2011).
An extra high dose of erythropoietin fails to support the proliferation of erythropoietin dependent cell lines.
|
| |
Cytotechnology,
63,
101-109.
|
|
|
|
|
|
|
A.J.Brooks,
and
M.J.Waters
(2010).
The growth hormone receptor: mechanism of activation and clinical implications.
|
| |
Nat Rev Endocrinol,
6,
515-525.
|
|
|
|
|
|
|
S.Mirza,
A.Walker,
J.Chen,
J.M.Murphy,
and
I.G.Young
(2010).
The Ig-like domain of human GM-CSF receptor alpha plays a critical role in cytokine binding and receptor activation.
|
| |
Biochem J,
426,
307-317.
|
|
|
|
|
|
|
T.J.Cammett,
S.J.Jun,
E.B.Cohen,
F.N.Barrera,
D.M.Engelman,
and
D.Dimaio
(2010).
Construction and genetic selection of small transmembrane proteins that activate the human erythropoietin receptor.
|
| |
Proc Natl Acad Sci U S A,
107,
3447-3452.
|
|
|
|
|
|
|
J.Nickel,
W.Sebald,
J.C.Groppe,
and
T.D.Mueller
(2009).
Intricacies of BMP receptor assembly.
|
| |
Cytokine Growth Factor Rev,
20,
367-377.
|
|
|
|
|
|
|
W.C.Peng,
X.Lin,
and
J.Torres
(2009).
The strong dimerization of the transmembrane domain of the fibroblast growth factor receptor (FGFR) is modulated by C-terminal juxtamembrane residues.
|
| |
Protein Sci,
18,
450-459.
|
|
|
|
|
|
|
W.Liu,
M.Kawahara,
H.Ueda,
and
T.Nagamune
(2009).
The influence of domain structures on the signal transduction of chimeric receptors derived from the erythropoietin receptor.
|
| |
J Biochem,
145,
575-584.
|
|
|
|
|
|
|
G.Skiniotis,
P.J.Lupardus,
M.Martick,
T.Walz,
and
K.C.Garcia
(2008).
Structural organization of a full-length gp130/LIF-R cytokine receptor transmembrane complex.
|
| |
Mol Cell,
31,
737-748.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
M.Cardó-Vila,
A.J.Zurita,
R.J.Giordano,
J.Sun,
R.Rangel,
L.Guzman-Rojas,
C.D.Anobom,
A.P.Valente,
F.C.Almeida,
J.Lahdenranta,
M.G.Kolonin,
W.Arap,
and
R.Pasqualini
(2008).
A ligand peptide motif selected from a cancer patient is a receptor-interacting site within human interleukin-11.
|
| |
PLoS ONE,
3,
e3452.
|
|
|
|
|
|
|
S.L.LaPorte,
Z.S.Juo,
J.Vaclavikova,
L.A.Colf,
X.Qi,
N.M.Heller,
A.D.Keegan,
and
K.C.Garcia
(2008).
Molecular and structural basis of cytokine receptor pleiotropy in the interleukin-4/13 system.
|
| |
Cell,
132,
259-272.
|
|
|
PDB codes:
|
|
|
|
|
|
|
|
S.W.Rowlinson,
H.Yoshizato,
J.L.Barclay,
A.J.Brooks,
S.N.Behncken,
L.M.Kerr,
K.Millard,
K.Palethorpe,
K.Nielsen,
J.Clyde-Smith,
J.F.Hancock,
and
M.J.Waters
(2008).
An agonist-induced conformational change in the growth hormone receptor determines the choice of signalling pathway.
|
| |
Nat Cell Biol,
10,
740-747.
|
|
|
|
|
|
|
R.Matadeen,
W.C.Hon,
J.K.Heath,
E.Y.Jones,
and
S.Fuller
(2007).
The dynamics of signal triggering in a gp130-receptor complex.
|
| |
Structure,
15,
441-448.
|
|
|
|
|
|
|
S.Liu,
S.Liu,
X.Zhu,
H.Liang,
A.Cao,
Z.Chang,
and
L.Lai
(2007).
Nonnatural protein-protein interaction-pair design by key residues grafting.
|
| |
Proc Natl Acad Sci U S A,
104,
5330-5335.
|
|
|
|
|
|
|
C.D.Krause,
N.Lavnikova,
J.Xie,
E.Mei,
O.V.Mirochnitchenko,
Y.Jia,
R.M.Hochstrasser,
and
S.Pestka
(2006).
Preassembly and ligand-induced restructuring of the chains of the IFN-gamma receptor complex: the roles of Jak kinases, Stat1 and the receptor chains.
|
| |
Cell Res,
16,
55-69.
|
|
|
|
|
|
|
C.D.Krause,
W.He,
S.Kotenko,
and
S.Pestka
(2006).
Modulation of the activation of Stat1 by the interferon-gamma receptor complex.
|
| |
Cell Res,
16,
113-123.
|
|
|
|
|
|
|
J.M.Kramer,
L.Yi,
F.Shen,
A.Maitra,
X.Jiao,
T.Jin,
and
S.L.Gaffen
(2006).
Evidence for ligand-independent multimerization of the IL-17 receptor.
|
| |
J Immunol,
176,
711-715.
|
|
|
|
|
|
|
H.M.Hermanns,
G.Müller-Newen,
P.C.Heinrich,
and
S.Haan
(2005).
Bow to your partner for signaling.
|
| |
Nat Struct Mol Biol,
12,
476-478.
|
|
|
|
|
|
|
K.F.Kubatzky,
W.Liu,
K.Goldgraben,
C.Simmerling,
S.O.Smith,
and
S.N.Constantinescu
(2005).
Structural requirements of the extracellular to transmembrane domain junction for erythropoietin receptor function.
|
| |
J Biol Chem,
280,
14844-14854.
|
|
|
|
|
|
|
S.Krause,
D.Würdemann,
A.Wentzel,
A.Christmann,
H.Fehr,
H.Kolmar,
and
K.Friedrich
(2004).
Bacteria displaying interleukin-4 mutants stimulate mammalian cells and reflect the biological activities of variant soluble cytokines.
|
| |
Chembiochem,
5,
804-810.
|
|
|
|
|
|
|
S.Pestka,
C.D.Krause,
D.Sarkar,
M.R.Walter,
Y.Shi,
and
P.B.Fisher
(2004).
Interleukin-10 and related cytokines and receptors.
|
| |
Annu Rev Immunol,
22,
929-979.
|
|
|
|
|
|
|
X.Cheng,
M.Kinosaki,
M.Takami,
Y.Choi,
H.Zhang,
and
R.Murali
(2004).
Disabling of receptor activator of nuclear factor-kappaB (RANK) receptor complex by novel osteoprotegerin-like peptidomimetics restores bone loss in vivo.
|
| |
J Biol Chem,
279,
8269-8277.
|
|
|
|
|
|
|
F.Lühder,
Y.Huang,
K.M.Dennehy,
C.Guntermann,
I.Müller,
E.Winkler,
T.Kerkau,
S.Ikemizu,
S.J.Davis,
T.Hanke,
and
T.Hünig
(2003).
Topological requirements and signaling properties of T cell-activating, anti-CD28 antibody superagonists.
|
| |
J Exp Med,
197,
955-966.
|
|
|
|
|
|
|
H.Jingami,
S.Nakanishi,
and
K.Morikawa
(2003).
Structure of the metabotropic glutamate receptor.
|
| |
Curr Opin Neurobiol,
13,
271-278.
|
|
|
|
|
|
|
M.Kawahara,
H.Ueda,
S.Morita,
K.Tsumoto,
I.Kumagai,
and
T.Nagamune
(2003).
Bypassing antibiotic selection: positive screening of genetically modified cells with an antigen-dependent proliferation switch.
|
| |
Nucleic Acids Res,
31,
e32.
|
|
|
|
|
|
|
N.Seubert,
Y.Royer,
J.Staerk,
K.F.Kubatzky,
V.Moucadel,
S.Krishnakumar,
S.O.Smith,
and
S.N.Constantinescu
(2003).
Active and inactive orientations of the transmembrane and cytosolic domains of the erythropoietin receptor dimer.
|
| |
Mol Cell,
12,
1239-1250.
|
|
|
|
|
|
|
S.N.Constantinescu,
T.Keren,
W.P.Russ,
I.Ubarretxena-Belandia,
Y.Malka,
K.F.Kubatzky,
D.M.Engelman,
H.F.Lodish,
and
Y.I.Henis
(2003).
The erythropoietin receptor transmembrane domain mediates complex formation with viral anemic and polycythemic gp55 proteins.
|
| |
J Biol Chem,
278,
43755-43763.
|
|
|
|
|
|
|
S.S.Sidhu,
W.J.Fairbrother,
and
K.Deshayes
(2003).
Exploring protein-protein interactions with phage display.
|
| |
Chembiochem,
4,
14-25.
|
|
|
|
|
|
|
A.Usacheva,
R.Sandoval,
P.Domanski,
S.V.Kotenko,
K.Nelms,
M.A.Goldsmith,
and
O.R.Colamonici
(2002).
Contribution of the Box 1 and Box 2 motifs of cytokine receptors to Jak1 association and activation.
|
| |
J Biol Chem,
277,
48220-48226.
|
|
|
|
|
|
|
B.C.Jones,
N.J.Logsdon,
K.Josephson,
J.Cook,
P.A.Barry,
and
M.R.Walter
(2002).
Crystal structure of human cytomegalovirus IL-10 bound to soluble human IL-10R1.
|
| |
Proc Natl Acad Sci U S A,
99,
9404-9409.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
J.S.Greiser,
C.Stross,
P.C.Heinrich,
I.Behrmann,
and
H.M.Hermanns
(2002).
Orientational constraints of the gp130 intracellular juxtamembrane domain for signaling.
|
| |
J Biol Chem,
277,
26959-26965.
|
|
|
|
|
|
|
K.Morikawa
(2002).
[Ligand recognition mechanism of G-CSF receptor and metabotropic glutamate receptor]
|
| |
Yakugaku Zasshi,
122,
855-868.
|
|
|
|
|
|
|
M.Graille,
S.Harrison,
M.P.Crump,
S.C.Findlow,
N.G.Housden,
B.H.Muller,
N.Battail-Poirot,
G.Sibaï,
B.J.Sutton,
M.J.Taussig,
C.Jolivet-Reynaud,
M.G.Gore,
and
E.A.Stura
(2002).
Evidence for plasticity and structural mimicry at the immunoglobulin light chain-protein L interface.
|
| |
J Biol Chem,
277,
47500-47506.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
P.S.Mischel,
J.A.Umbach,
S.Eskandari,
S.G.Smith,
C.B.Gundersen,
and
G.A.Zampighi
(2002).
Nerve growth factor signals via preexisting TrkA receptor oligomers.
|
| |
Biophys J,
83,
968-976.
|
|
|
|
|
|
|
R.Adar,
E.Monsonego-Ornan,
P.David,
and
A.Yayon
(2002).
Differential activation of cysteine-substitution mutants of fibroblast growth factor receptor 3 is determined by cysteine localization.
|
| |
J Bone Miner Res,
17,
860-868.
|
|
|
|
|
|
|
J.R.Cochran,
D.Aivazian,
T.O.Cameron,
and
L.J.Stern
(2001).
Receptor clustering and transmembrane signaling in T cells.
|
| |
Trends Biochem Sci,
26,
304-310.
|
|
|
|
|
|
|
P.S.Subramaniam,
M.M.Green,
J.Larkin,
B.A.Torres,
and
H.M.Johnson
(2001).
Nuclear translocation of IFN-gamma is an intrinsic requirement for its biologic activity and can be driven by a heterologous nuclear localization sequence.
|
| |
J Interferon Cytokine Res,
21,
951-959.
|
|
|
|
|
|
|
S.N.Constantinescu,
L.J.Huang,
H.Nam,
and
H.F.Lodish
(2001).
The erythropoietin receptor cytosolic juxtamembrane domain contains an essential, precisely oriented, hydrophobic motif.
|
| |
Mol Cell,
7,
377-385.
|
|
|
|
|
|
|
S.N.Constantinescu,
T.Keren,
M.Socolovsky,
H.Nam,
Y.I.Henis,
and
H.F.Lodish
(2001).
Ligand-independent oligomerization of cell-surface erythropoietin receptor is mediated by the transmembrane domain.
|
| |
Proc Natl Acad Sci U S A,
98,
4379-4384.
|
|
|
|
|
|
|
A.G.Cochran
(2000).
Antagonists of protein-protein interactions.
|
| |
Chem Biol,
7,
R85-R94.
|
|
|
|
|
|
|
C.A.Bell,
J.A.Tynan,
K.C.Hart,
A.N.Meyer,
S.C.Robertson,
and
D.J.Donoghue
(2000).
Rotational coupling of the transmembrane and kinase domains of the Neu receptor tyrosine kinase.
|
| |
Mol Biol Cell,
11,
3589-3599.
|
|
|
|
|
|
|
E.J.Sundberg,
and
R.A.Mariuzza
(2000).
Luxury accommodations: the expanding role of structural plasticity in protein-protein interactions.
|
| |
Structure,
8,
R137-R142.
|
|
|
|
|
|
|
E.Y.Jones
(2000).
The tumour necrosis factor receptor family: life or death choices.
|
| |
Curr Opin Struct Biol,
10,
644-648.
|
|
|
|
|
|
|
G.Müller-Newen,
A.Küster,
J.Wijdenes,
F.Schaper,
and
P.C.Heinrich
(2000).
Studies on the interleukin-6-type cytokine signal transducer gp130 reveal a novel mechanism of receptor activation by monoclonal antibodies.
|
| |
J Biol Chem,
275,
4579-4586.
|
|
|
|
|
|
|
M.C.Deller,
and
E.Yvonne Jones
(2000).
Cell surface receptors.
|
| |
Curr Opin Struct Biol,
10,
213-219.
|
|
|
|
|
|
|
M.Degano,
K.C.Garcia,
V.Apostolopoulos,
M.G.Rudolph,
L.Teyton,
and
I.A.Wilson
(2000).
A functional hot spot for antigen recognition in a superagonist TCR/MHC complex.
|
| |
Immunity,
12,
251-261.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
S.G.Miller
(2000).
Discovery of cytokine mimics using cell-based systems.
|
| |
Drug Discov Today,
5,
77-83.
|
|
|
|
|
|
|
S.Maliartchouk,
T.Debeir,
N.Beglova,
A.C.Cuello,
K.Gehring,
and
H.U.Saragovi
(2000).
Genuine monovalent ligands of TrkA nerve growth factor receptors reveal a novel pharmacological mechanism of action.
|
| |
J Biol Chem,
275,
9946-9956.
|
|
|
|
|
|
|
S.N.Behncken,
N.Billestrup,
R.Brown,
J.Amstrup,
B.Conway-Campbell,
and
M.J.Waters
(2000).
Growth hormone (GH)-independent dimerization of GH receptor by a leucine zipper results in constitutive activation.
|
| |
J Biol Chem,
275,
17000-17007.
|
|
|
|
|
|
|
C.Wiesmann,
and
A.M.de Vos
(1999).
Putting two and two together: crystal structure of the FGF-receptor complex.
|
| |
Structure,
7,
R251-R255.
|
|
|
|
|
|
|
D.K.Hendrix,
T.E.Klein,
I.D.Kuntz,
and
T.E.Klien
(1999).
Macromolecular docking of a three-body system: the recognition of human growth hormone by its receptor.
|
| |
Protein Sci,
8,
1010-1022.
|
|
|
|
|
|
|
G.Jiang,
and
T.Hunter
(1999).
Receptor signaling: when dimerization is not enough.
|
| |
Curr Biol,
9,
R568-R571.
|
|
|
|
|
|
|
I.A.Wilson,
and
L.K.Jolliffe
(1999).
The structure, organization, activation and plasticity of the erythropoietin receptor.
|
| |
Curr Opin Struct Biol,
9,
696-704.
|
|
|
|
|
|
|
I.Remy,
I.A.Wilson,
and
S.W.Michnick
(1999).
Erythropoietin receptor activation by a ligand-induced conformation change.
|
| |
Science,
283,
990-993.
|
|
|
|
|
|
|
K.E.Mogensen,
M.Lewerenz,
J.Reboul,
G.Lutfalla,
and
G.Uzé
(1999).
The type I interferon receptor: structure, function, and evolution of a family business.
|
| |
J Interferon Cytokine Res,
19,
1069-1098.
|
|
|
|
|
|
|
O.Livnah,
E.A.Stura,
S.A.Middleton,
D.L.Johnson,
L.K.Jolliffe,
and
I.A.Wilson
(1999).
Crystallographic evidence for preformed dimers of erythropoietin receptor before ligand activation.
|
| |
Science,
283,
987-990.
|
|
|
PDB code:
|
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|
|
|
|
|
S.A.Middleton,
F.P.Barbone,
D.L.Johnson,
R.L.Thurmond,
Y.You,
F.J.McMahon,
R.Jin,
O.Livnah,
J.Tullai,
F.X.Farrell,
M.A.Goldsmith,
I.A.Wilson,
and
L.K.Jolliffe
(1999).
Shared and unique determinants of the erythropoietin (EPO) receptor are important for binding EPO and EPO mimetic peptide.
|
| |
J Biol Chem,
274,
14163-14169.
|
|
|
|
|
|
|
S.N.Behncken,
and
M.J.Waters
(1999).
Molecular recognition events involved in the activation of the growth hormone receptor by growth hormone.
|
| |
J Mol Recognit,
12,
355-362.
|
|
|
|
|
|
|
S.S.Watowich,
K.D.Liu,
X.Xie,
S.Y.Lai,
A.Mikami,
G.D.Longmore,
and
M.A.Goldsmith
(1999).
Oligomerization and scaffolding functions of the erythropoietin receptor cytoplasmic tail.
|
| |
J Biol Chem,
274,
5415-5421.
|
|
|
|
|
|
|
M.D.Ballinger,
and
J.A.Wells
(1998).
Will any dimer do?
|
| |
Nat Struct Biol,
5,
938-940.
|
|
|
|
|
|
The most recent references are shown first.
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Where a reference describes a PDB structure, the PDB
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shown on the right.
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