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PDBsum entry 2hmh
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Cytokine regulator
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PDB id
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2hmh
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References listed in PDB file
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Key reference
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Title
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Structural basis for phosphotyrosine recognition by suppressor of cytokine signaling-3.
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Authors
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E.Bergamin,
J.Wu,
S.R.Hubbard.
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Ref.
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Structure, 2006,
14,
1285-1292.
[DOI no: ]
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PubMed id
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Abstract
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Suppressor of cytokine signaling (SOCS) proteins are indispensable negative
regulators of cytokine-stimulated Janus kinase (JAK)-signal transducer and
activator of transcription (STAT) signaling pathways. SOCS proteins (SOCS1-7 and
CIS) consist of a variable N-terminal region, a central Src homology-2 (SH2)
domain, and a C-terminal SOCS box. The N-terminal region in SOCS1 and SOCS3
includes the so-called kinase inhibitory region that has been shown to inhibit
the catalytic activity of JAK2. Here, we present a crystal structure at 2.0 A
resolution of the N-terminally extended SH2 domain of SOCS3 in complex with its
phosphopeptide target on the cytokine receptor gp130. The structure reveals that
major insertions in the EF and BG loops of the SOCS3 SH2 domain are responsible
for binding to gp130 with high affinity and specificity. In addition, the
structure provides insights into the possible mechanisms by which SOCS3 and
SOCS1 inhibit JAK2 kinase activity.
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Figure 1.
Figure 1. Crystal Structure of SOCS3Δ in Complex with the
gp130(pTyr757) Phosphopeptide
(A) Ribbon diagram of SOCS3Δ
with the bound gp130 phosphopeptide shown in stick
representation. The secondary structural elements for the SH2
domain are labeled; α helices are colored purple, β strands
are colored cyan, and loops are colored gray. Carbon atoms in
the gp130 phosphopeptide are colored yellow, oxygen atoms are
red, nitrogen atoms are blue, and the phosphate atom is black.
The gray spheres represent disordered residues in the BG loop.
The N and C termini for the SH2 domain and the phosphopeptide
are indicated by N and C, respectively, in gray (SOCS3Δ) and
yellow (gp130). The right panel is a view from 90° as
indicated; the EF and BG loops are labeled, and the side chain
of Tyr31 (on edge) of the kinase inhibitory region is shown.
This panel and Figures 2A, 2B, 3B, and 3C were rendered with
PyMOL (http://pymol.sourceforge.net).
(B) Molecular surface
representation of SOCS3Δ colored according to electrostatic
potential (blue, positive [+10 kT]; white, neutral; red,
negative [−10 kT]). Residues of the gp130 phosphopeptide are
labeled relative to pTyr757 (P). The course of the EF loop in
the SH2 domain is shown in gray. This panel was rendered with
GRASP (Nicholls et al., 1991).
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Figure 3.
Figure 3. Structure-Based Sequence Alignment and Structural
Comparisons
(A) Structural alignment of murine SOCS3Δ with
the SH2 domains of human Src (PDB code 1SPS) (Waksman et al.,
1993), human SHP2 (N-terminal SH2, PDB code 1AYA) (Lee et al.,
1994), and murine SOCS1 (predicted). Residues shaded in purple
reside in α helices, and residues shaded in cyan reside in β
strands. Disordered residues not included in the atomic model
are italicized. The residues in the BG loop that were deleted in
the SOCS3Δ construct are shaded in gray. Residues of the SOCS3
and SOCS1 kinase inhibitory region are underlined. Residues
colored blue make direct hydrogen bonds or salt bridges via
their side chains to the phosphate group of the bound
phosphopeptide (predicted for SOCS1), and residues colored red
make direct hydrogen bonds via their side chains to other
residues in the bound phosphopeptide (only present in
SOCS3Δ-gp130).
(B) Superposition (Cα trace) of the
SOCS3Δ-gp130(pTyr757) structure with the N-terminal SH2 domain
of SHP2 with bound phosphopeptide (PDB code 1AYA) (Lee et al.,
1994). Residues in βB, βC, and βD were used in the
superposition (rmsd = 0.28 Å for 20 Cα atoms). SOCS3Δ is
colored cyan, the gp130 phosphopeptide is colored yellow, the
SHP2 N-terminal SH2 domain is colored dark green, and the bound
phosphopeptide is colored light green. Select side chains of the
phosphopeptides are shown in stick representation: Val (P−2),
pTyr (P), Val (P+3), and His (P+5) (SOCS3 structure) or Pro
(P+5) (SHP2 structure).
(C) Superposition (Cα trace) of
the SOCS3Δ-gp130(pTyr757) crystal structure and the
SOCS3-gp130(pTyr757) NMR structure (PDB code 2BBU) (Babon et
al., 2006). The individual NMR structure with the lowest overall
rmsd (#18 in the 20-structure ensemble; rmsd = 4.3 Å for
115 Cα atoms) was used for the comparison. For the figure,
residues in βB, βC, and βD were superimposed (rmsd = 1.4
Å for 23 Cα atoms). SOCS3Δ and the gp130 phosphopeptide
from the crystal structure are colored cyan and yellow,
respectively, and SOCS3 and the gp130 phosphopeptide from the
NMR structure are colored dark green and light green,
respectively. For clarity, the  vert,
similar 30 residue PEST sequence at the beginning of the BG loop
has been omitted from the NMR structure. The beginning/end of
the omitted interval are indicated by green arrows, and the
beginning/end of the disordered region of the BG loop in the
SOCS3Δ crystal structure are indicated by cyan arrows. As in
(A), select side chains of the phosphopeptide are shown in stick
representation.
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The above figures are
reprinted
by permission from Cell Press:
Structure
(2006,
14,
1285-1292)
copyright 2006.
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