PDBsum entry: 3cxe

Cytokine

PDB id: 3cxe

Contents

Protein chains

412 a.a. *

105 a.a. *

116 a.a. *

Ligands

NAG-NAG-BMA

NAG ×2

* Residue conservation analysis

PDB id:

3cxe

Name:

Cytokine

Title:

Structure of the gm-csf receptor complex

Structure:

Cytokine receptor common subunit beta. Chain: a. Fragment: residues 25-438. Synonym: gm-csf/il-3/il-5 receptor common beta-chain, cd131 cdw131. Engineered: yes. Mutation: yes. Granulocyte-macrophage colony-stimulating factor. Chain: b.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: csf2rb, il3rb, il5rb. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Gene: csf2, gmcsf. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

3.30Å R-factor: 0.273 R-free: 0.317

Authors:

G.Hansen,T.R.Hercus,J.M.Woodcock,B.J.Mcclure,F.C.Stomski,Y.X W.J.Mckinstry,A.F.Lopez,M.W.Parker

Key ref:

G.Hansen et al. (2008). The structure of the GM-CSF receptor complex reveals a distinct mode of cytokine receptor activation. Cell, 134, 496-507. PubMed id: 18692472 DOI: 10.1016/j.cell.2008.05.053

Date:

24-Apr-08 Release date: 26-Aug-08

Protein chain

P32927  (IL3RB_HUMAN) -  Cytokine receptor common subunit beta

Seq: 897 a.a.

Struc: 412 a.a.*

Protein chain

P04141  (CSF2_HUMAN) -  Granulocyte-macrophage colony-stimulating factor

Seq: 144 a.a.

Struc: 105 a.a.

Protein chain

P15509  (CSF2R_HUMAN) -  Granulocyte-macrophage colony-stimulating factor receptor subunit alpha

Seq: 400 a.a.

Struc: 116 a.a.*

* PDB and UniProt seqs differ at 18 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 

• Cellular component: extracellular region (3 terms)
• Biological process: positive regulation of podosome assembly (16 terms)
• Biochemical function: protein binding (5 terms)

DOI no: 10.1016/j.cell.2008.05.053

Cell 134:496-507 (2008)

PubMed id: 18692472

The structure of the GM-CSF receptor complex reveals a distinct mode of cytokine receptor activation.

G.Hansen, T.R.Hercus, B.J.McClure, F.C.Stomski, M.Dottore, J.Powell, H.Ramshaw, J.M.Woodcock, Y.Xu, M.Guthridge, W.J.McKinstry, A.F.Lopez, M.W.Parker.

ABSTRACT

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic cytokine that controls the production and function of blood cells, is deregulated in clinical conditions such as rheumatoid arthritis and leukemia, yet offers therapeutic value for other diseases. Its receptors are heterodimers consisting of a ligand-specific alpha subunit and a betac subunit that is shared with the interleukin (IL)-3 and IL-5 receptors. How signaling is initiated remains an enigma. We report here the crystal structure of the human GM-CSF/GM-CSF receptor ternary complex and its assembly into an unexpected dodecamer or higher-order complex. Importantly, mutagenesis of the GM-CSF receptor at the dodecamer interface and functional studies reveal that dodecamer formation is required for receptor activation and signaling. This unusual form of receptor assembly likely applies also to IL-3 and IL-5 receptors, providing a structural basis for understanding their mechanism of activation and for the development of therapeutics.

Selected figure(s)

Figure 1.
Figure 1. Structure of the GM-CSF Receptor Ternary Complex
GM-CSF is highlighted in blue and GMRα in yellow. One monomer of βc is shown in magenta (chain a) and the other in green (chain b). Labels correspond to domain names. Orthogonal views show how the complex would sit on the membrane surface. The bottom panel shows the view of the receptor when looking toward the membrane and the top panel shows a side-on view with the molecule sitting on a membrane surface. Observed N-linked carbohydrates are shown as sticks. Disordered peptides that connect the C termini of each chain to the membrane are shown as dashed lines. This and the following figures were prepared with PyMOL (DeLano, 2002).

Figure 3.
Figure 3. The Dodecamer Complex
(A) View of the dodecamer when looking toward the membrane surface. Coloring as in Figure 1 with second hexamer in lighter shade. (A model of the complete domain 1 of GMRα [labeled αD1] was superimposed onto the partial model derived from the crystallographic data.) Also shown is the likely location of the GMRα knob domain. In the lower panel a simplified version of the upper panel highlights the arrangement of chains and domains. The chains of βc are labeled a to d and domains denoted with a “D.”
(B) Side-on (with respect to the membrane) view of the complex, highlighting peeled-away interaction surfaces between GMRα domain 2 and βc domain 4 of each hexamer (Site 4).

The above figures are reprinted by permission from Cell Press: Cell (2008, 134, 496-507) copyright 2008.

Figures were selected by the author.