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PDBsum entry 2erj
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protein ligands Protein-protein interface(s) links
Immune system/cytokine PDB id
2erj

 

 

 

 

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Contents
Protein chains
130 a.a. *
204 a.a. *
195 a.a. *
131 a.a. *
Ligands
NAG-NAG-BMA-FUC ×2
NAG-FUC
NAG-NAG-BMA ×2
NAG-NAG ×2
NAG-NAG-FUC
NAG ×4
* Residue conservation analysis
PDB id:
2erj
Name: Immune system/cytokine
Title: Crystal structure of the heterotrimeric interleukin-2 receptor in complex with interleukin-2
Structure: Interleukin-2 receptor alpha chain. Chain: a, e. Synonym: il-2 receptor alpha subunit, il-2-ra, il2-ra, p55, cd25, tac antigen. Engineered: yes. Mutation: yes. Interleukin-2 receptor beta chain. Chain: b, f. Synonym: il-2 receptor beta subunit, il-2-rb, p75, cd122.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: il2ra. Expressed in: trichoplusia ni. Expression_system_taxid: 7111. Gene: il2rb. Gene: il2rg. Gene: il2.
Biol. unit: Tetramer (from PQS)
Resolution:
3.00Å     R-factor:   0.223     R-free:   0.263
Authors: E.W.Debler,D.J.Stauber,I.A.Wilson
Key ref:
D.J.Stauber et al. (2006). Crystal structure of the IL-2 signaling complex: paradigm for a heterotrimeric cytokine receptor. Proc Natl Acad Sci U S A, 103, 2788-2793. PubMed id: 16477002 DOI: 10.1073/pnas.0511161103
Date:
25-Oct-05     Release date:   21-Feb-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P01589  (IL2RA_HUMAN) -  Interleukin-2 receptor subunit alpha from Homo sapiens
Seq:
Struc: 		272 a.a.
130 a.a.*
Protein chains
Pfam   ArchSchema ?
P14784  (IL2RB_HUMAN) -  Interleukin-2 receptor subunit beta from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		551 a.a.
204 a.a.*
Protein chains
Pfam   ArchSchema ?
P31785  (IL2RG_HUMAN) -  Cytokine receptor common subunit gamma from Homo sapiens
Seq:
Struc: 		369 a.a.
195 a.a.*
Protein chains
Pfam   ArchSchema ?
P60568  (IL2_HUMAN) -  Interleukin-2 from Homo sapiens
Seq:
Struc: 		153 a.a.
131 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 6 residue positions (black crosses)

 

 
DOI no: 10.1073/pnas.0511161103 Proc Natl Acad Sci U S A 103:2788-2793 (2006)
PubMed id: 16477002  
 
 
Crystal structure of the IL-2 signaling complex: paradigm for a heterotrimeric cytokine receptor.
D.J.Stauber, E.W.Debler, P.A.Horton, K.A.Smith, I.A.Wilson.
 
  ABSTRACT  
 
IL-2 is a cytokine that functions as a growth factor and central regulator in the immune system and mediates its effects through ligand-induced hetero-trimerization of the receptor subunits IL-2R alpha, IL-2R beta, and gamma(c). Here, we describe the crystal structure of the trimeric assembly of the human IL-2 receptor ectodomains in complex with IL-2 at 3.0 A resolution. The quaternary structure is consistent with a stepwise assembly from IL-2/IL-2R alpha to IL-2/IL-2R alpha/IL-2R beta to IL-2/IL-2R alpha/IL-2R beta/gamma(c). The IL-2R alpha subunit forms the largest of the three IL-2/IL-2R interfaces, which, together with the high abundance of charge-charge interactions, correlates well with the rapid association rate and high-affinity interaction of IL-2R alpha with IL-2 at the cell surface. Surprisingly, IL-2R alpha makes no contacts with IL-2R beta or gamma(c), and only minor changes are observed in the IL-2 structure in response to receptor binding. These findings support the principal role of IL-2R alpha to deliver IL-2 to the signaling complex and act as regulator of signal transduction. Cooperativity in assembly of the final quaternary complex is easily explained by the extraordinarily extensive set of interfaces found within the fully assembled IL-2 signaling complex, which nearly span the entire length of the IL-2R beta and gamma(c) subunits. Helix A of IL-2 wedges tightly between IL-2R beta and gamma(c) to form a three-way junction that coalesces into a composite binding site for the final gamma(c) recruitment. The IL-2/gamma(c) interface itself exhibits the smallest buried surface and the fewest hydrogen bonds in the complex, which is consistent with its promiscuous use in other cytokine receptor complexes.
 
  Selected figure(s)  
 
Figure 2.
Fig. 2. Interface between IL-2R and IL-2. Open-book representation of the IL-2/IL-2R interface. The electrostatic potential was mapped onto the molecular surface and contoured at ±35kT/eV (blue/red). The interface features a hydrophobic center, flanked by a large number of salt bridges and other polar contacts. The strong electrostatic component of this interaction serves to rapidly capture IL-2 and, thus, to dominate the k[on] rate of IL-2 binding to the IL-2R. 		Figure 5.
Fig. 5. Three-way junction between IL-2, IL-2R , and [c]. IL-2 (yellow ribbon representation), IL-2R , and [c] (the surfaces are colored as in Figs. 3 and 4) form a three-way junction at the heart of the high-affinity IL-2 signaling complex. The network of residues that mediate these contacts (colored red) provides a compelling structural basis for cooperativity in the IL-2/IL-2R complex assembly.
 
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20820193 H.Yang, J.Wang, J.Du, C.Zhong, D.Zhang, H.Guo, Y.Guo, and J.Ding (2010).
Structural basis of immunosuppression by the therapeutic antibody daclizumab.
  Cell Res, 20, 1361-1371.
PDB codes: 3nfp 3nfs
19818367 S.W.Stonier, and K.S.Schluns (2010).
Trans-presentation: a novel mechanism regulating IL-15 delivery and responses.
  Immunol Lett, 127, 85-92.  
20161451 C.L.McClendon, G.Friedland, D.L.Mobley, H.Amirkhani, and M.P.Jacobson (2009).
Quantifying Correlations Between Allosteric Sites in Thermodynamic Ensembles.
  J Chem Theory Comput, 5, 2486-2502.  
19269352 D.Gómez-Martín, M.Díaz-Zamudio, J.C.Crispín, and J.Alcocer-Varela (2009).
Interleukin 2 and systemic lupus erythematosus: beyond the transcriptional regulatory net abnormalities.
  Autoimmun Rev, 9, 34-39.  
19816193 D.V.Liu, L.M.Maier, D.A.Hafler, and K.D.Wittrup (2009).
Engineered interleukin-2 antagonists for the inhibition of regulatory T cells.
  J Immunother, 32, 887-894.  
19447046 J.Wang, L.S.Wicker, and P.Santamaria (2009).
IL-2 and its high-affinity receptor: genetic control of immunoregulation and autoimmunity.
  Semin Immunol, 21, 363-371.  
19818738 M.H.Pham, N.Kondapalli, C.L.Reckord, and P.D.Foglesong (2009).
Interleukin-2 induces the activities of DNA topoisomerase I and DNA topoisomerase II in HuT 78 cells.
  Biochem Biophys Res Commun, 390, 577-580.  
19352505 R.Dey, K.Ji, Z.Liu, and L.Chen (2009).
A cytokine-cytokine interaction in the assembly of higher-order structure and activation of the interleukine-3:receptor complex.
  PLoS ONE, 4, e5188.  
19436055 T.R.Hercus, D.Thomas, M.A.Guthridge, P.G.Ekert, J.King-Scott, M.W.Parker, and A.F.Lopez (2009).
The granulocyte-macrophage colony-stimulating factor receptor: linking its structure to cell signaling and its role in disease.
  Blood, 114, 1289-1298.  
18817510 X.Wang, P.Lupardus, S.L.Laporte, and K.C.Garcia (2009).
Structural biology of shared cytokine receptors.
  Annu Rev Immunol, 27, 29-60.  
19710453 X.Zhu, W.D.Marcus, W.Xu, H.I.Lee, K.Han, J.O.Egan, J.L.Yovandich, P.R.Rhode, and H.C.Wong (2009).
Novel human interleukin-15 agonists.
  J Immunol, 183, 3598-3607.  
18458113 E.Mortier, T.Woo, R.Advincula, S.Gozalo, and A.Ma (2008).
IL-15Ralpha chaperones IL-15 to stable dendritic cell membrane complexes that activate NK cells via trans presentation.
  J Exp Med, 205, 1213-1225.  
18692472 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, and M.W.Parker (2008).
The structure of the GM-CSF receptor complex reveals a distinct mode of cytokine receptor activation.
  Cell, 134, 496-507.
PDB code: 3cxe
18062768 T.R.Malek (2008).
The biology of interleukin-2.
  Annu Rev Immunol, 26, 453-479.  
18829468 Y.Malka, T.Hornakova, Y.Royer, L.Knoops, J.C.Renauld, S.N.Constantinescu, and Y.I.Henis (2008).
Ligand-independent homomeric and heteromeric complexes between interleukin-2 or -9 receptor subunits and the gamma chain.
  J Biol Chem, 283, 33569-33577.  
17559173 D.M.Soper, D.J.Kasprowicz, and S.F.Ziegler (2007).
IL-2Rbeta links IL-2R signaling with Foxp3 expression.
  Eur J Immunol, 37, 1817-1826.  
17129182 M.A.Williams, and M.J.Bevan (2007).
Effector and memory CTL differentiation.
  Annu Rev Immunol, 25, 171-192.  
17643103 M.Chirifu, C.Hayashi, T.Nakamura, S.Toma, T.Shuto, H.Kai, Y.Yamagata, S.J.Davis, and S.Ikemizu (2007).
Crystal structure of the IL-15-IL-15Ralpha complex, a cytokine-receptor unit presented in trans.
  Nat Immunol, 8, 1001-1007.
PDB codes: 2z3q 2z3r
16911870 H.P.Kim, J.Imbert, and W.J.Leonard (2006).
Both integrated and differential regulation of components of the IL-2/IL-2 receptor system.
  Cytokine Growth Factor Rev, 17, 349-366.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.

 

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