spacer
spacer

PDBsum entry 2b5i

Go to PDB code: 
protein ligands Protein-protein interface(s) links
Cytokine/cytokine receptor PDB id
2b5i
Jmol
Contents
Protein chains
120 a.a. *
196 a.a. *
191 a.a. *
122 a.a. *
Ligands
NAG-NAG ×2
NAG ×2
Waters ×171
* Residue conservation analysis
PDB id:
2b5i
Name: Cytokine/cytokine receptor
Title: Cytokine receptor complex
Structure: Interleukin-2. Chain: a. Synonym: il-2, t-cell growth factor, tcgf, aldesleukin. Engineered: yes. Interleukin-2 receptor beta chain. Chain: b. Synonym: il-2 receptor, p70-75, high affinity il-2 receptor subunit, cd122 antigen. Engineered: yes.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: il2. Expressed in: trichoplusia ni. Expression_system_taxid: 7111. Gene: il2rb. Gene: il2rg. Gene: il2ra.
Biol. unit: Tetramer (from PQS)
Resolution:
2.30Å     R-factor:   0.225     R-free:   0.269
Authors: X.Wang,M.Rickert,K.C.Garcia
Key ref:
X.Wang et al. (2005). Structure of the quaternary complex of interleukin-2 with its alpha, beta, and gammac receptors. Science, 310, 1159-1163. PubMed id: 16293754 DOI: 10.1126/science.1117893
Date:
28-Sep-05     Release date:   29-Nov-05    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P60568  (IL2_HUMAN) -  Interleukin-2
Seq:
Struc:
153 a.a.
120 a.a.
Protein chain
Pfam   ArchSchema ?
P14784  (IL2RB_HUMAN) -  Interleukin-2 receptor subunit beta
Seq:
Struc:
 
Seq:
Struc:
551 a.a.
196 a.a.*
Protein chain
Pfam   ArchSchema ?
P31785  (IL2RG_HUMAN) -  Cytokine receptor common subunit gamma
Seq:
Struc:
369 a.a.
191 a.a.*
Protein chain
Pfam   ArchSchema ?
P01589  (IL2RA_HUMAN) -  Interleukin-2 receptor subunit alpha
Seq:
Struc:
272 a.a.
122 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   3 terms 
  Biological process     immune system process   34 terms 
  Biochemical function     carbohydrate binding     8 terms  

 

 
DOI no: 10.1126/science.1117893 Science 310:1159-1163 (2005)
PubMed id: 16293754  
 
 
Structure of the quaternary complex of interleukin-2 with its alpha, beta, and gammac receptors.
X.Wang, M.Rickert, K.C.Garcia.
 
  ABSTRACT  
 
Interleukin-2 (IL-2) is an immunoregulatory cytokine that acts through a quaternary receptor signaling complex containing alpha (IL-2Ralpha), beta (IL-2Rbeta), and common gamma chain (gc) receptors. In the structure of the quaternary ectodomain complex as visualized at a resolution of 2.3 angstroms, the binding of IL-2Ralpha to IL-2 stabilizes a secondary binding site for presentation to IL-2Rbeta. gammac is then recruited to the composite surface formed by the IL-2/IL-2Rbeta complex. Consistent with its role as a shared receptor for IL-4, IL-7, IL-9, IL-15, and IL-21, gammac forms degenerate contacts with IL-2. The structure of gammac provides a rationale for loss-of-function mutations found in patients with X-linked severe combined immunodeficiency diseases (X-SCID). This complex structure provides a framework for other gammac-dependent cytokine-receptor interactions and for the engineering of improved IL-2 therapeutics.
 
  Selected figure(s)  
 
Figure 3.
Fig. 3. A polar interface and hydration layer between IL-2 and IL-2Rß. (A) All interactions between IL-2 and IL-2Rß. The buried water molecules in the interface are shown as green spheres. The hydrogen bonds between IL-2 and IL-2Rß are in black; those between water molecules and protein atoms are in green. (B) Close-up view of the shape complementarity in the interface, as viewed from above.
Figure 5.
Fig. 5. Extensive receptor-receptor contact between IL-2Rß and [c]. (A) Surface representation of the quaternary complex shows the shape complementarity in the IL-2Rß/ [c] interface. (B) Hydrogen-bonding interactions between IL-2Rß and [c].
 
  The above figures are reprinted by permission from the AAAs: Science (2005, 310, 1159-1163) copyright 2005.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
22446627 A.M.Levin, D.L.Bates, A.M.Ring, C.Krieg, J.T.Lin, L.Su, I.Moraga, M.E.Raeber, G.R.Bowman, P.Novick, V.S.Pande, C.G.Fathman, O.Boyman, and K.C.Garcia (2012).
Exploiting a natural conformational switch to engineer an interleukin-2 'superkine'.
  Nature, 484, 529-533.
PDB codes: 3qaz 3qb1
22343569 O.Boyman, and J.Sprent (2012).
The role of interleukin-2 during homeostasis and activation of the immune system.
  Nat Rev Immunol, 12, 180-190.  
21109548 G.Béhar, V.Solé, A.Defontaine, M.Maillasson, A.Quéméner, Y.Jacques, and C.Tellier (2011).
Evolution of interleukin-15 for higher E. coli expression and solubility.
  Protein Eng Des Sel, 24, 283-290.  
21532597 S.C.Wuest, J.H.Edwan, J.F.Martin, S.Han, J.S.Perry, C.M.Cartagena, E.Matsuura, D.Maric, T.A.Waldmann, and B.Bielekova (2011).
A role for interleukin-2 trans-presentation in dendritic cell-mediated T cell activation in humans, as revealed by daclizumab therapy.
  Nat Med, 17, 604-609.  
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
20554759 J.Suthaus, A.Tillmann, I.Lorenzen, E.Bulanova, S.Rose-John, and J.Scheller (2010).
Forced homo- and heterodimerization of all gp130-type receptor complexes leads to constitutive ligand-independent signaling and cytokine-independent growth.
  Mol Biol Cell, 21, 2797-2807.  
19141282 C.A.McElroy, J.A.Dohm, and S.T.Walsh (2009).
Structural and biophysical studies of the human IL-7/IL-7Ralpha complex.
  Structure, 17, 54-65.
PDB codes: 3di2 3di3
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.  
19956099 H.Q.Qu, J.P.Bradfield, A.Bélisle, S.F.Grant, H.Hakonarson, and C.Polychronakos (2009).
The type I diabetes association of the IL2RA locus.
  Genes Immun, 10, S42-S48.  
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.  
19576999 L.Bloom, and V.Calabro (2009).
FN3: a new protein scaffold reaches the clinic.
  Drug Discov Today, 14, 949-955.  
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.  
18243092 A.Zdanov, and A.Wlodawer (2008).
A new look at cytokine signaling.
  Cell, 132, 179-181.  
18674934 C.A.Sabatos, J.Doh, S.Chakravarti, R.S.Friedman, P.G.Pandurangi, A.J.Tooley, and M.F.Krummel (2008).
A synaptic basis for paracrine interleukin-2 signaling during homotypic T cell interaction.
  Immunity, 29, 238-248.  
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
18621751 H.P.Carroll, V.Paunovic, and M.Gadina (2008).
Signalling, inflammation and arthritis: Crossed signals: the role of interleukin-15 and -18 in autoimmunity.
  Rheumatology (Oxford), 47, 1269-1277.  
17979192 K.A.Denessiouk, A.I.Denesyuk, and M.S.Johnson (2008).
Negative modulation of signal transduction via interleukin splice variation.
  Proteins, 71, 751-770.  
18243101 S.L.LaPorte, Z.S.Juo, J.Vaclavikova, L.A.Colf, X.Qi, N.M.Heller, A.D.Keegan, and K.C.Garcia (2008).
Molecular and structural basis of cytokine receptor pleiotropy in the interleukin-4/13 system.
  Cell, 132, 259-272.
PDB codes: 3bpl 3bpn 3bpo
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.  
18958714 H.Fujii (2007).
Mechanisms of Signal Transduction from Receptors of Type I and Type II Cytokines.
  J Immunotoxicol, 4, 69-76.  
17255936 H.Liu, X.Chen, P.J.Focia, and X.He (2007).
Structural basis for stem cell factor-KIT signaling and activation of class III receptor tyrosine kinases.
  EMBO J, 26, 891-901.
PDB codes: 2o26 2o27
17936914 M.A.Burchill, J.Yang, K.B.Vang, and M.A.Farrar (2007).
Interleukin-2 receptor signaling in regulatory T cell development and homeostasis.
  Immunol Lett, 114, 1-8.  
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
17571248 R.Amato, M.Menniti, V.Agosti, R.Boito, N.Costa, H.M.Bond, V.Barbieri, P.Tagliaferri, S.Venuta, and N.Perrotti (2007).
IL-2 signals through Sgk1 and inhibits proliferation and apoptosis in kidney cancer cells.
  J Mol Med, 85, 707-721.  
17604854 R.E.Chen, and J.Thorner (2007).
Function and regulation in MAPK signaling pathways: lessons learned from the yeast Saccharomyces cerevisiae.
  Biochim Biophys Acta, 1773, 1311-1340.  
17001647 A.Quéméner, J.Bernard, E.Mortier, A.Plet, Y.Jacques, and V.Tran (2006).
Docking of human interleukin-15 to its specific receptor alpha chain: correlation between molecular modeling and mutagenesis experimental data.
  Proteins, 65, 623-636.  
17032757 C.D.Thanos, W.L.DeLano, and J.A.Wells (2006).
Hot-spot mimicry of a cytokine receptor by a small molecule.
  Proc Natl Acad Sci U S A, 103, 15422-15427.
PDB code: 1qvn
16477002 D.J.Stauber, E.W.Debler, P.A.Horton, K.A.Smith, and I.A.Wilson (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.
PDB code: 2erj
16893988 D.T.Nardelli, T.F.Warner, S.M.Callister, and R.F.Schell (2006).
Anti-CD25 antibody treatment of mice vaccinated and challenged with Borrelia spp. does not exacerbate arthritis but inhibits borreliacidal antibody production.
  Clin Vaccine Immunol, 13, 884-891.  
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.  
  16751420 J.Huang, K.W.Kerstann, M.Ahmadzadeh, Y.F.Li, M.El-Gamil, S.A.Rosenberg, and P.F.Robbins (2006).
Modulation by IL-2 of CD70 and CD27 expression on CD8+ T cells: importance for the therapeutic effectiveness of cell transfer immunotherapy.
  J Immunol, 176, 7726-7735.  
16907989 K.A.Smith (2006).
The structure of IL2 bound to the three chains of the IL2 receptor and how signaling occurs.
  Med Immunol, 5, 3.  
16467871 K.A.Smith (2006).
The quantal theory of immunity.
  Cell Res, 16, 11-19.  
16972794 O.Hecht, A.J.Dingley, A.Schwanter, S.Ozbek, S.Rose-John, and J.Grötzinger (2006).
The solution structure of the membrane-proximal cytokine receptor domain of the human interleukin-6 receptor.
  Biol Chem, 387, 1255-1259.
PDB code: 2arw
17015070 Z.P.Hu, X.X.Yang, S.Y.Chan, A.L.Xu, W.Duan, Y.Z.Zhu, F.S.Sheu, U.A.Boelsterli, E.Chan, Q.Zhang, J.C.Wang, P.L.Ee, H.L.Koh, M.Huang, and S.F.Zhou (2006).
St. John's wort attenuates irinotecan-induced diarrhea via down-regulation of intestinal pro-inflammatory cytokines and inhibition of intestinal epithelial apoptosis.
  Toxicol Appl Pharmacol, 216, 225-237.  
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.