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PDBsum entry 1iar
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protein Protein-protein interface(s) links
Cytokine/receptor PDB id
1iar

 

 

 

 

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Contents
Protein chains
129 a.a. *
188 a.a. *
Waters ×230
* Residue conservation analysis
PDB id:
1iar
Name: Cytokine/receptor
Title: Interleukin-4 / receptor alpha chain complex
Structure: Protein (interleukin-4). Chain: a. Engineered: yes. Protein (interleukin-4 receptor alpha chain). Chain: b. Fragment: extracellular domain. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Other_details: recombinant. Other_details: recombinant
Biol. unit: Dimer (from PQS)
Resolution:
2.30Å     R-factor:   0.218     R-free:   0.289
Authors: T.Hage,W.Sebald,P.Reinemer
Key ref:
T.Hage et al. (1999). Crystal structure of the interleukin-4/receptor alpha chain complex reveals a mosaic binding interface. Cell, 97, 271-281. PubMed id: 10219247 DOI: 10.1016/S0092-8674(00)80736-9
Date:
25-Feb-99     Release date:   03-Mar-00    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P05112  (IL4_HUMAN) -  Interleukin-4 from Homo sapiens
Seq:
Struc: 		153 a.a.
129 a.a.
Protein chain
Pfam   ArchSchema ?
P24394  (IL4RA_HUMAN) -  Interleukin-4 receptor subunit alpha from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		825 a.a.
188 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 

 
DOI no: 10.1016/S0092-8674(00)80736-9 Cell 97:271-281 (1999)
PubMed id: 10219247  
 
 
Crystal structure of the interleukin-4/receptor alpha chain complex reveals a mosaic binding interface.
T.Hage, W.Sebald, P.Reinemer.
 
  ABSTRACT  
 
Interleukin-4 (IL-4) is a principal regulatory cytokine during an immune response and a crucial determinant for allergy and asthma. IL-4 binds with high affinity and specificity to the ectodomain of the IL-4 receptor alpha chain (IL4-BP). Subsequently, this intermediate complex recruits the common gamma chain (gamma c), thereby initiating transmembrane signaling. The crystal structure of the intermediate complex between human IL-4 and IL4-BP was determined at 2.3 A resolution. It reveals a novel spatial orientation of the two proteins, a small but unexpected conformational change in the receptor-bound IL-4, and an interface with three separate clusters of trans-interacting residues. Novel insights on ligand binding in the cytokine receptor family and a paradigm for receptors of IL-2, IL-7, IL-9, and IL-15, which all utilize gamma c, are provided.
 
  Selected figure(s)  
 
Figure 2.
Figure 2. Structure of Receptor-Bound IL-4Ribbon representation illustrating conformational differences between free IL-4 (yellow, 1rcb [[55]; green, 1int [ [52]) and IL-4 in complex with IL4-BP (red, wild-type IL-4; blue, SeMet-IL-4).
Figure 4.
 
  The above figures are reprinted by permission from Cell Press: Cell (1999, 97, 271-281) copyright 1999.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21210100 T.Wang, W.Huang, M.M.Costa, S.A.Martin, and C.J.Secombes (2011).
Two copies of the genes encoding the subunits of putative interleukin (IL)-4/IL-13 receptors, IL-4Rα, IL-13Rα1 and IL-13Rα2, have been identified in rainbow trout (Oncorhynchus mykiss) and have complex patterns of expression and modulation.
  Immunogenetics, 63, 235-253.  
20849616 E.J.Helmreich (2010).
Ways and means of coping with uncertainties of the relationship of the genetic blue print to protein structure and function in the cell.
  Cell Commun Signal, 8, 26.  
20008102 S.A.Assi, T.Tanaka, T.H.Rabbitts, and N.Fernandez-Fuentes (2010).
PCRPi: Presaging Critical Residues in Protein interfaces, a new computational tool to chart hot spots in protein interfaces.
  Nucleic Acids Res, 38, e86.  
20078425 S.Mirza, A.Walker, J.Chen, J.M.Murphy, and I.G.Young (2010).
The Ig-like domain of human GM-CSF receptor alpha plays a critical role in cytokine binding and receptor activation.
  Biochem J, 426, 307-317.  
19671186 A.C.Schrimpe, and D.W.Wright (2009).
Differential gene expression mediated by 15-hydroxyeicosatetraenoic acid in LPS-stimulated RAW 264.7 cells.
  Malar J, 8, 195.  
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
19196002 G.Schreiber, G.Haran, and H.X.Zhou (2009).
Fundamental aspects of protein-protein association kinetics.
  Chem Rev, 109, 839-860.  
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.  
18243092 A.Zdanov, and A.Wlodawer (2008).
A new look at cytokine signaling.
  Cell, 132, 179-181.  
18560827 M.Ohtani, N.Hayashi, K.Hashimoto, T.Nakanishi, and J.M.Dijkstra (2008).
Comprehensive clarification of two paralogous interleukin 4/13 loci in teleost fish.
  Immunogenetics, 60, 383-397.  
17932929 R.Alsallaq, and H.X.Zhou (2008).
Electrostatic rate enhancement and transient complex of protein-protein association.
  Proteins, 71, 320-335.  
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
18294864 T.Ishino, A.E.Harrington, M.Zaks-Zilberman, J.J.Scibek, and I.Chaiken (2008).
Slow-dissociation effect of common signaling subunit beta c on IL5 and GM-CSF receptor assembly.
  Cytokine, 42, 179-190.  
17295905 D.Weber, A.Kotzsch, J.Nickel, S.Harth, A.Seher, U.Mueller, W.Sebald, and T.D.Mueller (2007).
A silent H-bond can be mutationally activated for high-affinity interaction of BMP-2 and activin type IIB receptor.
  BMC Struct Biol, 7, 6.
PDB codes: 2h62 2h64
  17909291 J.Wickham, and S.T.Walsh (2007).
Crystallization and preliminary X-ray diffraction of human interleukin-7 bound to unglycosylated and glycosylated forms of its alpha-receptor.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 63, 865-869.  
17565991 K.Bondensgaard, J.Breinholt, D.Madsen, D.H.Omkvist, L.Kang, A.Worsaae, P.Becker, C.B.Schiødt, and S.A.Hjorth (2007).
The existence of multiple conformers of interleukin-21 directs engineering of a superpotent analogue.
  J Biol Chem, 282, 23326-23336.
PDB code: 2oqp
17292839 R.Alsallaq, and H.X.Zhou (2007).
Prediction of protein-protein association rates from a transition-state theory.
  Structure, 15, 215-224.  
17947230 S.K.Olsen, N.Ota, S.Kishishita, M.Kukimoto-Niino, K.Murayama, H.Uchiyama, M.Toyama, T.Terada, M.Shirouzu, O.Kanagawa, and S.Yokoyama (2007).
Crystal Structure of the Interleukin-15{middle dot}Interleukin-15 Receptor {alpha} Complex: INSIGHTS INTO TRANS AND CIS PRESENTATION.
  J Biol Chem, 282, 37191-37204.
PDB code: 2psm
17009316 D.C.Fry (2006).
Protein-protein interactions as targets for small molecule drug discovery.
  Biopolymers, 84, 535-552.  
16856180 F.Dong, and H.X.Zhou (2006).
Electrostatic contribution to the binding stability of protein-protein complexes.
  Proteins, 65, 87.  
16377614 I.Lorenzen, A.J.Dingley, Y.Jacques, and J.Grötzinger (2006).
The structure of the interleukin-15 alpha receptor and its implications for ligand binding.
  J Biol Chem, 281, 6642-6647.
PDB code: 2ers
16640778 M.Kraich, M.Klein, E.Patiño, H.Harrer, J.Nickel, W.Sebald, and T.D.Mueller (2006).
A modular interface of IL-4 allows for scalable affinity without affecting specificity for the IL-4 receptor.
  BMC Biol, 4, 13.
PDB codes: 2b8u 2b8x 2b8y 2b8z 2b90 2b91 2d48
15701050 J.X.Cui, J.F.Ji, A.G.Lv, and W.F.Wu (2005).
Construction and expression of novel immunotoxin cpIL-4(13D)-PE38KDEL with increased activity.
  Biochemistry (Mosc), 70, 62-68.  
15870068 K.Arima, K.Sato, G.Tanaka, S.Kanaji, T.Terada, E.Honjo, R.Kuroki, Y.Matsuo, and K.Izuhara (2005).
Characterization of the interaction between interleukin-13 and interleukin-13 receptors.
  J Biol Chem, 280, 24915-24922.  
16340415 M.B.Yaffe (2005).
X-ray crystallography and structural biology.
  Crit Care Med, 33, S435-S440.  
15562516 N.Rekha, S.M.Machado, C.Narayanan, A.Krupa, and N.Srinivasan (2005).
Interaction interfaces of protein domains are not topologically equivalent across families within superfamilies: Implications for metabolic and signaling pathways.
  Proteins, 58, 339-353.  
15684085 S.L.Laporte, C.M.Forsyth, B.C.Cunningham, L.J.Miercke, D.Akhavan, and R.M.Stroud (2005).
De novo design of an IL-4 antagonist and its structure at 1.9 A.
  Proc Natl Acad Sci U S A, 102, 1889-1894.
PDB code: 1y4c
15985167 S.Pletnev, E.Magracheva, A.Wlodawer, and A.Zdanov (2005).
A model of the ternary complex of interleukin-10 with its soluble receptors.
  BMC Struct Biol, 5, 10.  
16293754 X.Wang, M.Rickert, and K.C.Garcia (2005).
Structure of the quaternary complex of interleukin-2 with its alpha, beta, and gammac receptors.
  Science, 310, 1159-1163.
PDB code: 2b5i
15060062 J.M.Murphy, S.C.Ford, J.E.Olsen, S.E.Gustin, P.D.Jeffrey, D.L.Ollis, and I.G.Young (2004).
Interleukin-3 binding to the murine betaIL-3 and human betac receptors involves functional epitopes formed by domains 1 and 4 of different protein chains.
  J Biol Chem, 279, 26500-26508.  
15064755 S.Keller, J.Nickel, J.L.Zhang, W.Sebald, and T.D.Mueller (2004).
Molecular recognition of BMP-2 and BMP receptor IA.
  Nat Struct Mol Biol, 11, 481-488.
PDB codes: 1reu 1rew
15174163 S.Krause, D.Würdemann, A.Wentzel, A.Christmann, H.Fehr, H.Kolmar, and K.Friedrich (2004).
Bacteria displaying interleukin-4 mutants stimulate mammalian cells and reflect the biological activities of variant soluble cytokines.
  Chembiochem, 5, 804-810.  
15032600 S.Pestka, C.D.Krause, D.Sarkar, M.R.Walter, Y.Shi, and P.B.Fisher (2004).
Interleukin-10 and related cytokines and receptors.
  Annu Rev Immunol, 22, 929-979.  
12525483 J.M.Murphy, S.C.Ford, U.M.Wiedemann, P.D.Carr, D.L.Ollis, and I.G.Young (2003).
A novel functional epitope formed by domains 1 and 4 of the human common beta-subunit is involved in receptor activation by granulocyte macrophage colony-stimulating factor and interleukin 5.
  J Biol Chem, 278, 10572-10577.  
12649439 S.D.Emerson, R.Palermo, C.M.Liu, J.W.Tilley, L.Chen, W.Danho, V.S.Madison, D.N.Greeley, G.Ju, and D.C.Fry (2003).
NMR characterization of interleukin-2 in complexes with the IL-2Ralpha receptor component, and with low molecular weight compounds that inhibit the IL-2/IL-Ralpha interaction.
  Protein Sci, 12, 811-822.  
14528293 Z.Kato, J.Jee, H.Shikano, M.Mishima, I.Ohki, H.Ohnishi, A.Li, K.Hashimoto, E.Matsukuma, K.Omoya, Y.Yamamoto, T.Yoneda, T.Hara, N.Kondo, and M.Shirakawa (2003).
The structure and binding mode of interleukin-18.
  Nat Struct Biol, 10, 966-971.
PDB code: 1j0s
11874464 J.L.Zhang, M.Buehner, and W.Sebald (2002).
Functional epitope of common gamma chain for interleukin-4 binding.
  Eur J Biochem, 269, 1490-1499.  
12440146 K.Morikawa (2002).
[Ligand recognition mechanism of G-CSF receptor and metabotropic glutamate receptor]
  Yakugaku Zasshi, 122, 855-868.  
11345195 C.J.Bagley, J.M.Woodcock, M.A.Guthridge, F.C.Stomski, and A.F.Lopez (2001).
Structural and functional hot spots in cytokine receptors.
  Int J Hematol, 73, 299-307.  
11488979 J.Zuegg, D.C.Webb, P.S.Foster, and M.G.Casarotto (2001).
Structural model of human IL-13 defines the spatial interactions with the IL-13Ralpha/IL-4Ralpha receptor.
  Immunol Cell Biol, 79, 332-339.
PDB code: 1j9u
11698684 L.C.Roisman, J.Piehler, J.Y.Trosset, H.A.Scheraga, and G.Schreiber (2001).
Structure of the interferon-receptor complex determined by distance constraints from double-mutant cycles and flexible docking.
  Proc Natl Acad Sci U S A, 98, 13231-13236.  
11526337 M.Hülsmeyer, C.Scheufler, and M.K.Dreyer (2001).
Structure of interleukin 4 mutant E9A suggests polar steering in receptor-complex formation.
  Acta Crystallogr D Biol Crystallogr, 57, 1334-1336.
PDB code: 1hzi
11250200 M.Randal, and A.A.Kossiakoff (2001).
The structure and activity of a monomeric interferon-gamma:alpha-chain receptor signaling complex.
  Structure, 9, 155-163.
PDB code: 1fyh
11207369 P.D.Carr, S.E.Gustin, A.P.Church, J.M.Murphy, S.C.Ford, D.A.Mann, D.M.Woltring, I.Walker, D.L.Ollis, and I.G.Young (2001).
Structure of the complete extracellular domain of the common beta subunit of the human GM-CSF, IL-3, and IL-5 receptors reveals a novel dimer configuration.
  Cell, 104, 291-300.
PDB code: 1gh7
11358507 S.E.Gustin, A.P.Church, S.C.Ford, D.A.Mann, P.D.Carr, D.L.Ollis, and I.G.Young (2001).
Expression, crystallization and derivatization of the complete extracellular domain of the beta(c) subunit of the human IL-5, IL-3 and GM-CSF receptors.
  Eur J Biochem, 268, 2905-2911.  
10899108 C.Yoon, S.C.Johnston, J.Tang, M.Stahl, J.F.Tobin, and W.S.Somers (2000).
Charged residues dominate a unique interlocking topography in the heterodimeric cytokine interleukin-12.
  EMBO J, 19, 3530-3541.
PDB codes: 1f42 1f45
10835339 J.Bravo, and J.K.Heath (2000).
Receptor recognition by gp130 cytokines.
  EMBO J, 19, 2399-2411.  
11058786 K.J.Kallen, J.Grötzinger, and S.Rose-John (2000).
New perspectives on the design of cytokines and growth factors.
  Trends Biotechnol, 18, 455-461.  
  10850801 L.Cosenza, A.Rosenbach, J.V.White, J.R.Murphy, and T.Smith (2000).
Comparative model building of interleukin-7 using interleukin-4 as a template: a structural hypothesis that displays atypical surface chemistry in helix D important for receptor activation.
  Protein Sci, 9, 916-926.  
10753817 M.C.Deller, and E.Yvonne Jones (2000).
Cell surface receptors.
  Curr Opin Struct Biol, 10, 213-219.  
11027984 P.Reinemer, W.Sebald, and A.Duschl (2000).
The Interleukin-4-Receptor: From Recognition Mechanism to Pharmacological Target Structure.
  Angew Chem Int Ed Engl, 39, 2834-2846.  
10799519 Y.Oshima, B.H.Joshi, and R.K.Puri (2000).
Conversion of interleukin-13 into a high affinity agonist by a single amino acid substitution.
  J Biol Chem, 275, 14375-14380.  
10607675 I.A.Wilson, and L.K.Jolliffe (1999).
The structure, organization, activation and plasticity of the erythropoietin receptor.
  Curr Opin Struct Biol, 9, 696-704.  
10494829 J.Grötzinger, T.Kernebeck, K.J.Kallen, and S.Rose-John (1999).
IL-6 type cytokine receptor complexes: hexamer, tetramer or both?
  Biol Chem, 380, 803-813.  
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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