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PDBsum entry 1ext
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Signalling protein
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PDB id
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1ext
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Contents |
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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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Structures of the extracellular domain of the type i tumor necrosis factor receptor.
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Authors
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J.H.Naismith,
T.Q.Devine,
T.Kohno,
S.R.Sprang.
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Ref.
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Structure, 1996,
4,
1251-1262.
[DOI no: ]
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PubMed id
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Note In the PDB file this reference is
annotated as "TO BE PUBLISHED".
The citation details given above were identified by an automated
search of PubMed on title and author
names, giving a
perfect match.
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Abstract
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BACKGROUND: Tumor necrosis factor (TNF) is a powerful cytokine that is involved
in immune and pro-inflammatory responses. Two TNF receptors that belong to the
cysteine-rich low affinity nerve growth factor receptor family (TNF-R1 and
TNF-R2) are the sole mediators of TNF signalling. Signalling is thought to occur
when a trimer of TNF binds to the extracellular domains of two or three receptor
molecules, which permits aggregation and activation of the cytoplasmic domains.
The complex is then internalized within an endocytic vesicle, whereupon it
dissociates at low pH. Structure of the soluble extracellular domain of the
receptor (sTNF-R1) both in the unliganded and TNF-bound state have previously
been determined. In both instances, the fourth subdomain of the receptor was
found to be partly disordered. In the unliganded state at pH 7.5, the
extracellular domain forms two distinct types of dimer, parallel and
antiparallel; the antiparallel dimer occludes the TNF-binding. RESULTS: We have
determined the structure of sTNF-R1 in two crystal forms in high salt at pH 3.7.
The orthorhombic crystals diffract to 1.85 ånd the entire polypeptide is well
ordered. In contrast, the C-terminal 32 residues are disordered in the hexagonal
crystals. In the orthorhombic form, these residues exhibit a topology and
disulphide connectivity that differs from the other three cysteine-rich domains
in the molecule. In both forms, the interface is considerably more extensive
than that used in complex formation with LTalpha. This 'low pH' dimer is
different from both of the dimers observed in crystals grown at pH 7.5.
CONCLUSIONS: The occurrence of the antiparallel dimers in both low pH crystal
forms suggest that they are not an artefact of crystal packing. Such dimers may
form in the low pH environment of the endosome. Because the dimer contact
surface occludes the TNF-binding site, formation of this dimer would dissociate
the TNF-receptor complex within the endosome. Three of the four cysteine-rich
domains of TNF-R1 are constructed from two distinct structural modules, termed
A1 and B2. The fourth subdomain comprises an A1 module followed by an unusual C2
module. Although the orientation of these modules with respect to each other is
sensitive to crystal packing, ligand binding, pH and ionic strength, the modules
are structurally well conserved between and within the known sTNF-R1 structures.
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Figure 1.
Figure 1. The complete structure of the monomer of sTNF-R1. (a)
A stereo diagram of the numbered Cα trace of the sTNF-R1
molecule found at pH 3.7. (b) A ribbon representation of the
structure with disulphide bonds shown as yellow spheres,
prepared with RASTER3D [31]. Subdomains one and three are in red
and subdomains two and four in orange. Figure 1. The
complete structure of the monomer of sTNF-R1. (a) A stereo
diagram of the numbered Cα trace of the sTNF-R1 molecule found
at pH 3.7. (b) A ribbon representation of the structure with
disulphide bonds shown as yellow spheres, prepared with RASTER3D
[[4]31]. Subdomains one and three are in red and subdomains two
and four in orange.
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Figure 3.
Figure 3. Two orthogonal views of the low pH dimer that is the
asymmetric unit of the P2[1]2[1]2[1] crystal form. Careful
examination of the figure shows that the interaction between
subdomain one and subdomain four is closer at one end of the
dimer than the other. (Figure prepared using RASTER3D [31].) The
color scheme for one monomer is the same as in Figure 1. The
other monomer is colored dark blue (subdomains one and three)
and bright blue (subdomains two and four). Figure 3. Two
orthogonal views of the low pH dimer that is the asymmetric unit
of the P2[1]2[1]2[1] crystal form. Careful examination of the
figure shows that the interaction between subdomain one and
subdomain four is closer at one end of the dimer than the other.
(Figure prepared using RASTER3D [[3]31].) The color scheme for
one monomer is the same as in [4]Figure 1. The other monomer is
colored dark blue (subdomains one and three) and bright blue
(subdomains two and four).
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The above figures are
reprinted
by permission from Cell Press:
Structure
(1996,
4,
1251-1262)
copyright 1996.
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Secondary reference #1
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Title
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Crystallographic evidence for dimerization of unliganded tumor necrosis factor receptor.
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Authors
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J.H.Naismith,
T.Q.Devine,
B.J.Brandhuber,
S.R.Sprang.
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Ref.
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J Biol Chem, 1995,
270,
13303-13307.
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PubMed id
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Secondary reference #2
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Title
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Two crystal forms of the extracellular domain of type i tumor necrosis factor receptor.
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Authors
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L.E.Rodseth,
B.Brandhuber,
T.Q.Devine,
M.J.Eck,
K.Hale,
J.H.Naismith,
S.R.Sprang.
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Ref.
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J Mol Biol, 1994,
239,
332-335.
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PubMed id
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Secondary reference #3
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Title
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Crystal structure of the soluble human 55 kd tnf receptor-Human tnf beta complex: implications for tnf receptor activation.
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Authors
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D.W.Banner,
A.D'Arcy,
W.Janes,
R.Gentz,
H.J.Schoenfeld,
C.Broger,
H.Loetscher,
W.Lesslauer.
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Ref.
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Cell, 1993,
73,
431-445.
[DOI no: ]
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PubMed id
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