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PDBsum entry 1p9m
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Signaling protein/cytokine
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PDB id
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1p9m
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Contents |
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298 a.a.
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163 a.a.
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201 a.a.
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Hexameric structure and assembly of the interleukin-6/il-6 alpha-Receptor/gp130 complex.
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Authors
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M.J.Boulanger,
D.C.Chow,
E.E.Brevnova,
K.C.Garcia.
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Ref.
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Science, 2003,
300,
2101-2104.
[DOI no: ]
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PubMed id
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Abstract
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Interleukin-6 (IL-6) is an immunoregulatory cytokine that activates a
cell-surface signaling assembly composed of IL-6, the IL-6 alpha-receptor
(IL-6Ralpha), and the shared signaling receptor gp130. The 3.65
angstrom-resolution structure of the extracellular signaling complex reveals a
hexameric, interlocking assembly mediated by a total of 10 symmetry-related,
thermodynamically coupled interfaces. Assembly of the hexameric complex occurs
sequentially: IL-6 is first engaged by IL-6Ralpha and then presented to gp130in
the proper geometry to facilitate a cooperative transition into the
high-affinity, signaling-competent hexamer. The quaternary structures of other
IL-6/IL-12 family signaling complexes are likely constructed by means of a
similar topological blueprint.
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Figure 1.
Fig. 1. Structure of the human Il-6/IL-6R  /gp130 hexameric
complex. (A) Schematized view of the domain structure of IL-6,
IL-6R , and gp130. (B)
Top view of a SigmaA-weighted 2F[obs] - F[calc] electron density
map contoured at 2  of the hexamer.
The gp130 molecules are colored in cyan and blue, IL-6R molecules are
colored green and purple, and IL-6 molecules are colored pink
and red. The coloring scheme is maintained in all figures. (C)
Tilted side view of the hexamer rotated  90° toward the
viewer and tilted on the diagonal from (B). The five unique
interfaces are labeled as sites I, IIa, IIb, IIIa, and IIIb.
Figures were prepared with MOLSCRIPT (21) and Raster3D (22).
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Figure 3.
Fig. 3. Stepwise energetic and structural assembly of the
functional human IL-6 hexamer signaling complex. Isothermal
titration calorimetry (ITC) was used to measure the
thermodynamic parameters for each step in the hexamer assembly
pathway. The ITC titrations are designated as follows: site I:
IL-6 and IL-6R forming a binary
complex; site II: single-chain (sc) IL-6/IL-6R and gp130 D2D3
form a nonsignaling binary complex in the absence of the gp130
D1 domain; sites II and III: scIL-6/IL-6R and gp130 D1D2D3
form the signaling-competent hexamer; sites II and III 6 domain:
scIL-6/IL-6R and gp130
D1D2D3D4D5D6 resulting in the hexamer with the three
membrane-proximal domains of gp130. As discussed in the text,
the single-chain version of the IL-6/R complex was used
for these measurements to deconvolute the trimolecular
equilibrium (i.e., IL-6 + IL-6R + gp130) into a
bimolecular interaction event (i.e., single-chain IL-6/IL-6R
+ gp130).
Thermodynamic parameters for each titration are provided in
tabular format. Surfaces are calculated from the coordinates of
the hexamer components. The D1 domains of IL-6R are included as
schematic modules.
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The above figures are
reprinted
by permission from the AAAs:
Science
(2003,
300,
2101-2104)
copyright 2003.
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