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protein Protein-protein interface(s) links
Immune system PDB id
1z92
Jmol
Contents
Protein chains
121 a.a. *
123 a.a. *
* Residue conservation analysis
PDB id:
1z92
Name: Immune system
Title: Structure of interleukin-2 with its alpha receptor
Structure: Interleukin-2. Chain: a. Synonym: il-2, t-cell growth factor, tcgf, aldesleukin. Engineered: yes. Interleukin-2 receptor alpha chain. Chain: b. Fragment: extracellular domain. Synonym: il-2 receptor alpha subunit, p55, tac antigen, cd25 antigen.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: il2. Expressed in: trichoplusia ni. Expression_system_taxid: 7111. Gene: il2ra. Expression_system_taxid: 7111
Resolution:
2.80Å     R-factor:   0.233     R-free:   0.280
Authors: M.Rickert,X.Q.Wang,N.Goriatcheva,M.J.Boulanger,K.C.Garcia
Key ref:
M.Rickert et al. (2005). The structure of interleukin-2 complexed with its alpha receptor. Science, 308, 1477-1480. PubMed id: 15933202 DOI: 10.1126/science.1109745
Date:
31-Mar-05     Release date:   07-Jun-05    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P60568  (IL2_HUMAN) -  Interleukin-2
Seq:
Struc: 		153 a.a.
121 a.a.
Protein chain
Pfam   ArchSchema ?
P01589  (IL2RA_HUMAN) -  Interleukin-2 receptor subunit alpha
Seq:
Struc: 		272 a.a.
123 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   2 terms 
  Biological process     immune response   27 terms 
  Biochemical function     protein binding     8 terms  

 

 
DOI no: 10.1126/science.1109745 Science 308:1477-1480 (2005)
PubMed id: 15933202  
 
 
The structure of interleukin-2 complexed with its alpha receptor.
M.Rickert, X.Wang, M.J.Boulanger, N.Goriatcheva, K.C.Garcia.
 
  ABSTRACT  
 
Interleukin-2 (IL-2) is an immunoregulatory cytokine that binds sequentially to the alpha (IL-2Ralpha), beta (IL-2Rbeta), and common gamma chain (gammac) receptor subunits. Here we present the 2.8 angstrom crystal structure of a complex between human IL-2 and IL-2Ralpha, which interact in a docking mode distinct from that of other cytokine receptor complexes. IL-2Ralpha is composed of strand-swapped "sushi-like" domains, unlike the classical cytokine receptor fold. As a result of this domain swap, IL-2Ralpha uses a composite surface to dock into a groove on IL-2 that also serves as a binding site for antagonist drugs. With this complex, we now have representative structures for each class of hematopoietic cytokine receptor-docking modules.
 
  Selected figure(s)  
 
Figure 2.
Fig. 2. Domain swapping in IL-2R . (A) The IL-2R model is separated into D1 and D2 domains revealing the swapped A and B, and F and G strand locations, respectively. Semitransparent ovals in two diagrams of the separated sushi domains highlight the corresponding strands, which are involved in the strand swap. A surface representation of IL-2R in the center shows the complete receptor molecule. (B) A representative structure of a sushi domain, or CCP module [second domain of ß[2] glycoprotein-1 (Protein Data Bank entry 1QUB [PDB] )] (23, 32). The analogous strands to those involved in the strand swap between IL-2R D1 and D2 domain are blue and highlighted by a semitransparent oval. 		Figure 4.
Fig. 4. Comparison of receptor versus drug binding to IL-2. (A) "Footprint" representation of IL-2 interface as viewed through the IL-2R ß strands onto the IL-2 surface. Contact residues of IL-2R (green and cyan sticks) are projected onto the buried surface (orange) of IL-2. The hydrophobic anchor residues Phe^42 and Tyr45 of IL-2 are red. (B) Analogous footprint view of the drug compound 1 bound to IL-2. Compound 1 is depicted with blue sticks [Protein Data Bank entry name 1M48 [PDB] (17)] projected onto the buried surface (orange) of IL-2. Compound 1 uses IL-2 Phe^42 (red patch) as an anchor residue, thereby preventing IL-2R from binding to IL-2.
 
  The above figures are reprinted by permission from the AAAs: Science (2005, 308, 1477-1480) copyright 2005.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21519818 M.Guharoy, A.Pal, M.Dasgupta, and P.Chakrabarti (2011).
PRICE (PRotein Interface Conservation and Energetics): a server for the analysis of protein-protein interfaces.
  J Struct Funct Genomics, 12, 33-41.  
20796027 A.Láng, K.Szilágyi, B.Major, P.Gál, P.Závodszky, and A.Perczel (2010).
Intermodule cooperativity in the structure and dynamics of consecutive complement control modules in human C1r: structural biology.
  FEBS J, 277, 3986-3998.  
20007707 B.Li, L.Zhao, C.Wang, H.Guo, L.Wu, X.Zhang, W.Qian, H.Wang, and Y.Guo (2010).
The protein-protein interface evolution acts in a similar way to antibody affinity maturation.
  J Biol Chem, 285, 3865-3871.  
20544968 D.J.Diller, C.Humblet, X.Zhang, and L.M.Westerhoff (2010).
Computational alanine scanning with linear scaling semiempirical quantum mechanical methods.
  Proteins, 78, 2329-2337.  
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
20348246 Z.Tu, M.Cohen, H.Bu, and F.Lin (2010).
Tissue distribution and functional analysis of Sushi domain-containing protein 4.
  Am J Pathol, 176, 2378-2384.  
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.  
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.  
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.  
18680750 P.J.Lupardus, and K.C.Garcia (2008).
The structure of interleukin-23 reveals the molecular basis of p40 subunit sharing with interleukin-12.
  J Mol Biol, 382, 931-941.
PDB code: 3duh
  18235249 R.Zeiser, and R.S.Negrin (2008).
Interleukin-2 receptor downstream events in regulatory T cells: implications for the choice of immunosuppressive drug therapy.
  Cell Cycle, 7, 458-462.  
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
18062768 T.R.Malek (2008).
The biology of interleukin-2.
  Annu Rev Immunol, 26, 453-479.  
18573080 V.N.Uversky, C.J.Oldfield, and A.K.Dunker (2008).
Intrinsically disordered proteins in human diseases: introducing the D2 concept.
  Annu Rev Biophys, 37, 215-246.  
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.  
18075579 J.A.Wells, and C.L.McClendon (2007).
Reaching for high-hanging fruit in drug discovery at protein-protein interfaces.
  Nature, 450, 1001-1009.  
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
16551262 A.Ma, R.Koka, and P.Burkett (2006).
Diverse functions of IL-2, IL-15, and IL-7 in lymphoid homeostasis.
  Annu Rev Immunol, 24, 657-679.  
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.  
17009316 D.C.Fry (2006).
Protein-protein interactions as targets for small molecule drug discovery.
  Biopolymers, 84, 535-552.  
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
16580598 D.L.Simmons (2006).
What makes a good anti-inflammatory drug target?
  Drug Discov Today, 11, 210-219.  
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.  
16782791 P.J.Kundrotas, and E.Alexov (2006).
Electrostatic properties of protein-protein complexes.
  Biophys J, 91, 1724-1736.  
20476985 M.D.Pescovitz (2005).
Daclizumab: humanized monoclonal antibody to the interleukin-2 receptor.
  Expert Rev Clin Immunol, 1, 337-344.  
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.