PDBsum entry 2hmh

Cytokine regulator

PDB id: 2hmh

Contents

Protein chains

121 a.a. *

11 a.a. *

Waters ×58

* Residue conservation analysis

PDB id:

2hmh

Name:

Cytokine regulator

Title:

Crystal structure of socs3 in complex with gp130(ptyr757) phosphopeptide.

Structure:

Suppressor of cytokine signaling 3. Chain: a. Synonym: socs-3, cytokine-inducible sh2 protein 3, cis-3, protein ef- 10. Engineered: yes. Interleukin-6 receptor beta chain. Chain: b. Synonym: il-6r-beta, interleukin 6 signal transducer, membrane glycoprotein 130, gp130, cd130 antigen.

Source:

Mus musculus. House mouse. Organism_taxid: 10090. Gene: socs3. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Synthetic: yes. Other_details: this sequence occurs naturally in mice.

Biol. unit:

Dimer (from PQS)

Resolution:

2.00Å R-factor: 0.244 R-free: 0.291

Authors:

E.Bergamin,J.Wu,S.R.Hubbard

Key ref:

E.Bergamin et al. (2006). Structural basis for phosphotyrosine recognition by suppressor of cytokine signaling-3. Structure, 14, 1285-1292. PubMed id: 16905102 DOI: 10.1016/j.str.2006.06.011

Date:

11-Jul-06 Release date: 15-Aug-06

Protein chain

O35718  (SOCS3_MOUSE) -  Suppressor of cytokine signaling 3 from Mus musculus

Seq: 225 a.a.

Struc: 121 a.a.*

Protein chain

Q00560  (IL6RB_MOUSE) -  Interleukin-6 receptor subunit beta from Mus musculus

Seq: 917 a.a.

Struc: 11 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

DOI no: 10.1016/j.str.2006.06.011

Structure 14:1285-1292 (2006)

PubMed id: 16905102

Structural basis for phosphotyrosine recognition by suppressor of cytokine signaling-3.

E.Bergamin, J.Wu, S.R.Hubbard.

ABSTRACT

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.

Selected figure(s)

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).

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.

The above figures are reprinted by permission from Cell Press: Structure (2006, 14, 1285-1292) copyright 2006.

Figures were selected by an automated process.