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PDBsum entry 1n26
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Contents |
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* Residue conservation analysis
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PDB id:
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Cytokine
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Title:
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Crystal structure of the extra-cellular domains of human interleukin-6 receptor alpha chain
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Structure:
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Il-6 receptor alpha chain. Chain: a. Fragment: il-6r extral-cellular domains. Synonym: interleukin-6 receptor alpha chain. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: il6r. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Expression_system_cell_line: lec3.2.8.1.
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Resolution:
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2.40Å
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R-factor:
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0.220
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R-free:
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0.290
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Authors:
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J.N.Varghese,R.L.Moritz,M.-Z.Lou,A.Van Donkelaar,H.Ji,N.Ivancic, K.M.Branson,N.E.Hall,R.J.Simpson
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Key ref:
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J.N.Varghese
et al.
(2002).
Structure of the extracellular domains of the human interleukin-6 receptor alpha -chain.
Proc Natl Acad Sci U S A,
99,
15959-15964.
PubMed id:
DOI:
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Date:
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22-Oct-02
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Release date:
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18-Dec-02
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PROCHECK
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Headers
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References
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P08887
(IL6RA_HUMAN) -
Interleukin-6 receptor subunit alpha from Homo sapiens
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Seq:
Struc:
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468 a.a.
299 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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DOI no:
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Proc Natl Acad Sci U S A
99:15959-15964
(2002)
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PubMed id:
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Structure of the extracellular domains of the human interleukin-6 receptor alpha -chain.
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J.N.Varghese,
R.L.Moritz,
M.Z.Lou,
A.Van Donkelaar,
H.Ji,
N.Ivancic,
K.M.Branson,
N.E.Hall,
R.J.Simpson.
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ABSTRACT
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Dysregulated production of IL-6 and its receptor (IL-6R) are implicated in the
pathogenesis of multiple myeloma, autoimmune diseases and prostate cancer. The
IL-6R complex comprises two molecules each of IL-6, IL-6R, and the signaling
molecule, gp130. Here, we report the x-ray structure (2.4 A) of the IL-6R
ectodomains. The N-terminal strand of the Ig-like domain (D(1)) is
disulfide-bonded to domain D(2), and domains D(2) and D(3), the cytokine-binding
domain, are structurally similar to known cytokine-binding domains. The
head-to-tail packing of two closely associated IL-6R molecules observed in the
crystal may be representative of the configuration of the physiological dimer of
IL-6R and provides new insight into the architecture of the IL-6R complex.
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Selected figure(s)
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Figure 4.
Fig 4. The dimer interface of IL-6R showing the region of
interaction by red, green, blue, purple, and cyan areas
representing interdimeric distances (58) of less than 5, 4, 3,
2, and 1 Å, respectively. The view is rotated 180°
relative to the view in Fig. 1; the crystal twofold axis is
vertical, and the membrane is horizontal below the molecule.
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Figure 6.
Fig 6. (a) Space-filling model of the proposed hexameric
receptor complex, consisting of two molecules each of IL-6,
IL-6R, and gp130 chains (shown in purple and blue, light and
dark green, orange and red, respectively). IL-6 is labeled with
the binding sites I, II, and III. (b) A modular representation
of the hexameric complex (D[1]-D[6] are labeled 1-6) colored as
in a, but with the additional three fibronectin domains
(D[4]-D[6]) of gp130 that have not been modeled placed to
indicate how the association of the two D[5'] modules from both
gp130 molecules, under the "tunnel" of the IL-6R dimer, can
activate signaling by dimerization of the cytoplasmic domains
(white circles). The membrane proximal extracellular region of
IL-6R (49 residues) is shown as an extended chain connecting
IL-6R to the membrane.
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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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R.E.Gillilan,
M.J.Cook,
S.W.Cornaby,
and
D.H.Bilderback
(2010).
Microcrystallography using single-bounce monocapillary optics.
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J Synchrotron Radiat,
17,
227-236.
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M.Y.Wiesinger,
S.Haan,
S.Wüller,
M.E.Kauffmann,
T.Recker,
A.Küster,
P.C.Heinrich,
and
G.Müller-Newen
(2009).
Development of an IL-6 inhibitor based on the functional analysis of murine IL-6Ralpha(1).
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Chem Biol,
16,
783-794.
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X.Wang,
P.Lupardus,
S.L.Laporte,
and
K.C.Garcia
(2009).
Structural biology of shared cytokine receptors.
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Annu Rev Immunol,
27,
29-60.
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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.
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PLoS ONE,
3,
e3452.
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Y.Ohsugi,
and
T.Kishimoto
(2008).
The recombinant humanized anti-IL-6 receptor antibody tocilizumab, an innovative drug for the treatment of rheumatoid arthritis.
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Expert Opin Biol Ther,
8,
669-681.
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J.J.Velarde,
K.M.Varney,
K.G.Inman,
M.Farfan,
E.Dudley,
J.Fletcher,
D.J.Weber,
and
J.P.Nataro
(2007).
Solution structure of the novel dispersin protein of enteroaggregative Escherichia coli.
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Mol Microbiol,
66,
1123-1135.
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PDB code:
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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.
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Structure,
15,
441-448.
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T.Huyton,
J.G.Zhang,
C.S.Luo,
M.Z.Lou,
D.J.Hilton,
N.A.Nicola,
and
T.P.Garrett
(2007).
An unusual cytokine:Ig-domain interaction revealed in the crystal structure of leukemia inhibitory factor (LIF) in complex with the LIF receptor.
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Proc Natl Acad Sci U S A,
104,
12737-12742.
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PDB code:
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Y.Ohsugi
(2007).
Recent advances in immunopathophysiology of interleukin-6: an innovative therapeutic drug, tocilizumab (recombinant humanized anti-human interleukin-6 receptor antibody), unveils the mysterious etiology of immune-mediated inflammatory diseases.
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Biol Pharm Bull,
30,
2001-2006.
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O.Hecht,
A.J.Dingley,
A.Schwanter,
S.Ozbek,
S.Rose-John,
and
J.Grötzinger
(2006).
The solution structure of the membrane-proximal cytokine receptor domain of the human interleukin-6 receptor.
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Biol Chem,
387,
1255-1259.
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PDB code:
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B.E.Barton
(2005).
Interleukin-6 and new strategies for the treatment of cancer, hyperproliferative diseases and paraneoplastic syndromes.
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Expert Opin Ther Targets,
9,
737-752.
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D.Perret,
F.Rousseau,
V.Tran,
and
H.Gascan
(2005).
Reversal of some viral IL-6 electrostatic properties compared to IL-6 contributes to a loss of alpha receptor component recruitment.
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Proteins,
60,
14-26.
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G.Skiniotis,
M.J.Boulanger,
K.C.Garcia,
and
T.Walz
(2005).
Signaling conformations of the tall cytokine receptor gp130 when in complex with IL-6 and IL-6 receptor.
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Nat Struct Mol Biol,
12,
545-551.
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N.K.Krishna
(2005).
Identification of structural domains involved in astrovirus capsid biology.
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Viral Immunol,
18,
17-26.
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Y.Ohsugi,
and
N.Tsuchimoto
(2005).
[Pharmacological and clinical profile of anti-human IL-6 receptor antibody (tocilizumab, ACTEMRA), a novel therapeutic drug for Castleman's disease]
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Nippon Yakurigaku Zasshi,
126,
419-425.
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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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Links
