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PDBsum entry 1f45

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protein ligands Protein-protein interface(s) links
Cytokine/cytokine PDB id
1f45
Jmol
Contents
Protein chains
282 a.a. *
133 a.a. *
Ligands
NAG-NAG-MAN
Waters ×21
* Residue conservation analysis
PDB id:
1f45
Name: Cytokine/cytokine
Title: Human interleukin-12
Structure: Interleukin-12 beta chain. Chain: a. Fragment: residues 23-328. Engineered: yes. Mutation: yes. Interleukin-12 alpha chain. Chain: b. Fragment: residues 23-219. Engineered: yes.
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Expression_system_cell_line: cho.
Biol. unit: Tetramer (from PQS)
Resolution:
2.80Å     R-factor:   0.241     R-free:   0.284
Authors: C.Yoon,S.C.Johnston,J.Tang,J.F.Tobin,W.S.Somers
Key ref:
C.Yoon et al. (2000). Charged residues dominate a unique interlocking topography in the heterodimeric cytokine interleukin-12. EMBO J, 19, 3530-3541. PubMed id: 10899108 DOI: 10.1093/emboj/19.14.3530
Date:
07-Jun-00     Release date:   20-Jun-01    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P29460  (IL12B_HUMAN) -  Interleukin-12 subunit beta
Seq:
Struc:
328 a.a.
282 a.a.
Protein chain
Pfam   ArchSchema ?
P29459  (IL12A_HUMAN) -  Interleukin-12 subunit alpha
Seq:
Struc:
219 a.a.
133 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   6 terms 
  Biological process     negative regulation of growth of symbiont in host   63 terms 
  Biochemical function     protein binding     13 terms  

 

 
DOI no: 10.1093/emboj/19.14.3530 EMBO J 19:3530-3541 (2000)
PubMed id: 10899108  
 
 
Charged residues dominate a unique interlocking topography in the heterodimeric cytokine interleukin-12.
C.Yoon, S.C.Johnston, J.Tang, M.Stahl, J.F.Tobin, W.S.Somers.
 
  ABSTRACT  
 
Human interleukin-12 (IL-12, p70) is an early pro-inflammatory cytokine, comprising two disulfide-linked subunits, p35 and p40. We solved the crystal structures of monomeric human p40 at 2.5 A and the human p70 complex at 2.8 A resolution, which reveals that IL-12 is similar to class 1 cytokine-receptor complexes. They also include the first description of an N-terminal immunoglobulin-like domain, found on the p40 subunit. Several charged residues from p35 and p40 intercalate to form a unique interlocking topography, shown by mutagenesis to be critical for p70 formation. A central arginine residue from p35 projects into a deep pocket on p40, which may be an ideal target for a small molecule antagonist of IL-12 formation.
 
  Selected figure(s)  
 
Figure 1.
Figure 1 p40 resembles a soluble class 1 cytokine -receptor. N- and C-termini are labeled N and C, respectively, and the three domains are labeled D1, D2 and D3. The intrachain disulfide bonds (yellow), an N-linked sugar modification (red) and the WSXWS motif (magenta) are shown. The p40 loops that contact p35 (turquoise) are located at the apex between D2 and D3. Flexible loop regions are indicated by dotted lines. This and all subsequent figures (except Figures 3 and 7) were made using MOLSCRIPT (Kraulis, 1991) and Raster3D (Merritt and Bacon, 1997).
Figure 4.
Figure 4 Important charged interactions in the p35–p40 binding interface. (A) R189 (yellow) from p35 helix D projects into a deep, hydrophobic pocket composed of p40 loops 1, 5, 6 (thick) and 3 (thin). A buried hydrogen bonding network (dashes) connects R189 with D290 from p40 through a bound water (red sphere). (B) E181 in p40 is part of a second important charged interaction. Dashed lines indicate hydrogen bonding of p40 E181 with p35 residues R183 and T186. R183 is further stabilized by electrostatic interactions with p35 D108 in helix B.
 
  The above figures are reprinted from an Open Access publication published by Macmillan Publishers Ltd: EMBO J (2000, 19, 3530-3541) copyright 2000.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21330176 H.Q.Qu, S.P.Fisher-Hoch, and J.B.McCormick (2011).
Molecular immunity to mycobacteria: knowledge from the mutation and phenotype spectrum analysis of Mendelian susceptibility to mycobacterial diseases.
  Int J Infect Dis, 15, e305-e313.  
20974977 F.Rousseau, L.Basset, J.Froger, N.Dinguirard, S.Chevalier, and H.Gascan (2010).
IL-27 structural analysis demonstrates similarities with ciliary neurotrophic factor (CNTF) and leads to the identification of antagonistic variants.
  Proc Natl Acad Sci U S A, 107, 19420-19425.  
20551083 R.Sommavilla, N.Pasche, E.Trachsel, L.Giovannoni, C.Roesli, A.Villa, D.Neri, and M.Kaspar (2010).
Expression, engineering and characterization of the tumor-targeting heterodimeric immunocytokine F8-IL12.
  Protein Eng Des Sel, 23, 653-661.  
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.  
19395317 M.R.Simpson-Abelson, V.S.Purohit, W.M.Pang, V.Iyer, K.Odunsi, T.L.Demmy, S.J.Yokota, J.L.Loyall, R.J.Kelleher, S.Balu-Iyer, and R.B.Bankert (2009).
IL-12 delivered intratumorally by multilamellar liposomes reactivates memory T cells in human tumor microenvironments.
  Clin Immunol, 132, 71-82.  
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.  
18728012 F.Rousseau, S.Chevalier, C.Guillet, E.Ravon, C.Diveu, J.Froger, F.Barbier, L.Grimaud, and H.Gascan (2008).
Ciliary Neurotrophic Factor, Cardiotrophin-like Cytokine, and Neuropoietin Share a Conserved Binding Site on the Ciliary Neurotrophic Factor Receptor {alpha} Chain.
  J Biol Chem, 283, 30341-30350.  
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
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
15932623 A.Premraj, E.Sreekumar, B.Nautiyal, and T.J.Rasool (2005).
Interleukin-12 subunits p35 and p40 of Indian water buffalo (Bubalus bubalis) maintain high sequence homology with those of other ruminants.
  Int J Immunogenet, 32, 179-186.  
19956512 E.K.Park, Y.W.Kim, J.M.Lee, S.E.Namkoong, D.G.Kim, H.J.Chun, B.D.Han, S.M.Bae, H.S.Jin, J.I.Sin, and W.S.Ahn (2005).
Immunization with Adenoviral Vectors Carrying Recombinant IL-12 and E7 Enhanced the Antitumor Immunity against Human Papillomavirus 16-associated Tumor.
  Cancer Res Treat, 37, 63-70.  
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.  
15665625 A.Sharma, C.M.Harper, L.Hammer, R.E.Nair, E.Mathiowitz, and N.K.Egilmez (2004).
Characterization of cytokine-encapsulated controlled-release microsphere adjuvants.
  Cancer Biother Radiopharm, 19, 764-769.  
15272019 D.Perret, C.Guillet, G.Elson, J.Froger, H.Plun-Favreau, F.Rousseau, M.Chabbert, J.F.Gauchat, and H.Gascan (2004).
Two different contact sites are recruited by cardiotrophin-like cytokine (CLC) to generate the CLC/CLF and CLC/sCNTFRalpha composite cytokines.
  J Biol Chem, 279, 43961-43970.  
14720307 T.Schountz, R.Green, B.Davenport, A.Buniger, T.Richens, J.J.Root, F.Davidson, C.H.Calisher, and B.J.Beaty (2004).
Cloning and characterization of deer mouse (Peromyscus maniculatus) cytokine and chemokine cDNAs.
  BMC Immunol, 5, 1.  
14504285 C.Diveu, E.Lelièvre, D.Perret, A.H.Lak-Hal, J.Froger, C.Guillet, S.Chevalier, F.Rousseau, A.Wesa, L.Preisser, M.Chabbert, J.F.Gauchat, A.Galy, H.Gascan, and A.Morel (2003).
GPL, a novel cytokine receptor related to GP130 and leukemia inhibitory factor receptor.
  J Biol Chem, 278, 49850-49859.  
12707269 H.Plun-Favreau, D.Perret, C.Diveu, J.Froger, S.Chevalier, E.Lelièvre, H.Gascan, and M.Chabbert (2003).
Leukemia inhibitory factor (LIF), cardiotrophin-1, and oncostatin M share structural binding determinants in the immunoglobulin-like domain of LIF receptor.
  J Biol Chem, 278, 27169-27179.  
12529500 S.R.Leong, J.C.Chang, R.Ong, G.Dawes, W.P.Stemmer, and J.Punnonen (2003).
Optimized expression and specific activity of IL-12 by directed molecular evolution.
  Proc Natl Acad Sci U S A, 100, 1163-1168.  
11753820 C.Picard, C.Fieschi, F.Altare, S.Al-Jumaah, S.Al-Hajjar, J.Feinberg, S.Dupuis, C.Soudais, I.Z.Al-Mohsen, E.Génin, D.Lammas, D.S.Kumararatne, T.Leclerc, A.Rafii, H.Frayha, B.Murugasu, L.B.Wah, R.Sinniah, M.Loubser, E.Okamoto, A.Al-Ghonaium, H.Tufenkeji, L.Abel, and J.L.Casanova (2002).
Inherited interleukin-12 deficiency: IL12B genotype and clinical phenotype of 13 patients from six kindreds.
  Am J Hum Genet, 70, 336-348.  
12461182 J.N.Varghese, R.L.Moritz, M.Z.Lou, A.Van Donkelaar, H.Ji, N.Ivancic, K.M.Branson, N.E.Hall, and R.J.Simpson (2002).
Structure of the extracellular domains of the human interleukin-6 receptor alpha -chain.
  Proc Natl Acad Sci U S A, 99, 15959-15964.
PDB codes: 1n26 1n2q
11285233 H.Plun-Favreau, G.Elson, M.Chabbert, J.Froger, O.deLapeyrière, E.Lelièvre, C.Guillet, J.Hermann, J.F.Gauchat, H.Gascan, and S.Chevalier (2001).
The ciliary neurotrophic factor receptor alpha component induces the secretion of and is required for functional responses to cardiotrophin-like cytokine.
  EMBO J, 20, 1692-1703.  
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 code is shown on the right.