PDBsum entry 2r30

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Cytokine PDB id
Protein chain
116 a.a. *
* Residue conservation analysis
PDB id:
Name: Cytokine
Title: Crystal structure of human gitrl mutant
Structure: Tumor necrosis factor ligand superfamily member 18. Chain: a. Fragment: tnf homology domain. Synonym: glucocorticoid- induced tnf-related ligand, hgitrl, activation-inducible tnf-related ligand, aitrl. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: tnfsf18, aitrl, gitrl, tl6. Expressed in: escherichia coli. Expression_system_taxid: 562.
3.20Å     R-factor:   0.183     R-free:   0.239
Authors: K.Chattopadhyay,U.A.Ramagopal,S.G.Nathenson,S.C.Almo
Key ref:
K.Chattopadhyay et al. (2007). Assembly and structural properties of glucocorticoid-induced TNF receptor ligand: Implications for function. Proc Natl Acad Sci U S A, 104, 19452-19457. PubMed id: 18040044 DOI: 10.1073/pnas.0709264104
28-Aug-07     Release date:   13-Nov-07    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
Q9UNG2  (TNF18_HUMAN) -  Tumor necrosis factor ligand superfamily member 18
199 a.a.
116 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   1 term 
  Biological process     immune response   1 term 
  Biochemical function     tumor necrosis factor receptor binding     1 term  


DOI no: 10.1073/pnas.0709264104 Proc Natl Acad Sci U S A 104:19452-19457 (2007)
PubMed id: 18040044  
Assembly and structural properties of glucocorticoid-induced TNF receptor ligand: Implications for function.
K.Chattopadhyay, U.A.Ramagopal, A.Mukhopadhaya, V.N.Malashkevich, T.P.Dilorenzo, M.Brenowitz, S.G.Nathenson, S.C.Almo.
Glucocorticoid-induced TNF receptor ligand (GITRL), a recently identified member of the TNF family, binds to its receptor GITR on both effector and regulatory T cells and generates positive costimulatory signals implicated in a wide range of T cell functions. Structural analysis reveals that the human GITRL (hGITRL) ectodomain self-assembles into an atypical expanded homotrimer with sparse monomer-monomer interfaces. Consistent with the small intersubunit interfaces, hGITRL exhibits a relatively weak tendency to trimerize in solution and displays a monomer-trimer equilibrium not reported for other TNF family members. This unique assembly behavior has direct implications for hGITRL-GITR signaling, because enforced trimerization of soluble hGITRL ectodomain results in an approximately 100-fold increase in its receptor binding affinity and also in enhanced costimulatory activity. The apparent reduction in affinity that is the consequence of this dynamic equilibrium may represent a mechanism to realize the biologically optimal level of signaling through the hGITRL-GITR pathway, as opposed to the maximal achievable level.
  Selected figure(s)  
Figure 1.
Structure of the hGITRL ectodomain shows an atypical expanded architecture not observed in conventional TNF family members. (A) Ribbon diagram of hGITRL monomer showing the classic jelly-roll fold of the THD. The β-strands are labeled, and the N and C termini are marked. (B) Superposition of hGITRL (red) and hTNF-α (blue; 1TNF-A) monomers shows significant differences in the strand and loop lengths. hGITRL trimer (C) and hTNF-α (1TNF) trimer (D) are shown in side view as ribbon diagrams. C and D clearly demonstrate that the hGITRL trimer possesses an atypical expanded assembly and lacks the typical compact architecture of the conventional THDs.
Figure 3.
Enforced trimerization of hGITRL. (A) Molecular surface representation of the CC-hGITRL crystal structure shows that the fusion of the coiled-coil peptide to the N terminus of hGITRL does not induce any significant alterations in the global/local conformation of the protein. (B) Enforced trimerization of hGITRL augmented the in vitro T cell proliferative response. CD4^+ T cells were stimulated with hGITRL variants (5 μg/ml) in the presence of 30 ng/ml anti-CD3. Data shown are the mean (± SEM) of quadruplicate cultures and are representative of at least three independent assays.
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20228835 D.Cui, S.Wang, Y.Chen, J.Tong, J.Ma, L.Tang, X.Yang, Y.Shi, J.Tian, L.Lu, and H.Xu (2010).
An isoleucine-zipper motif enhances costimulation of human soluble trimeric GITR ligand.
  Cell Mol Immunol, 7, 316-322.  
20032458 E.Y.Won, K.Cha, J.S.Byun, D.U.Kim, S.Shin, B.Ahn, Y.H.Kim, A.J.Rice, T.Walz, B.S.Kwon, and H.S.Cho (2010).
The structure of the trimer of human 4-1BB ligand is unique among members of the tumor necrosis factor superfamily.
  J Biol Chem, 285, 9202-9210.
PDB code: 2x29
20139172 G.Liao, S.Nayak, J.R.Regueiro, S.B.Berger, C.Detre, X.Romero, Waal Malefyt, T.A.Chatila, R.W.Herzog, and C.Terhorst (2010).
GITR engagement preferentially enhances proliferation of functionally competent CD4+CD25+FoxP3+ regulatory T cells.
  Int Immunol, 22, 259-270.  
20948444 T.Burckhart, M.Thiel, H.Nishikawa, T.Wüest, D.Müller, A.Zippelius, G.Ritter, L.Old, H.Shiku, and C.Renner (2010).
Tumor-specific crosslinking of GITR as costimulation for immunotherapy.
  J Immunother, 33, 925-934.  
20331378 T.L.Mosbruger, P.Duggal, J.J.Goedert, G.D.Kirk, W.K.Hoots, L.H.Tobler, M.Busch, M.G.Peters, H.R.Rosen, D.L.Thomas, and C.L.Thio (2010).
Large-scale candidate gene analysis of spontaneous clearance of hepatitis C virus.
  J Infect Dis, 201, 1371-1380.  
20936139 T.Placke, H.G.Kopp, and H.R.Salih (2010).
Glucocorticoid-induced TNFR-related (GITR) protein and its ligand in antitumor immunity: functional role and therapeutic modulation.
  Clin Dev Immunol, 2010, 239083.  
19426233 K.Chattopadhyay, E.Lazar-Molnar, Q.Yan, R.Rubinstein, C.Zhan, V.Vigdorovich, U.A.Ramagopal, J.Bonanno, S.G.Nathenson, and S.C.Almo (2009).
Sequence, structure, function, immunity: structural genomics of costimulation.
  Immunol Rev, 229, 356-386.  
19390148 K.Chattopadhyay, U.A.Ramagopal, S.G.Nathenson, and S.C.Almo (2009).
1.8 A structure of murine GITR ligand dimer expressed in Drosophila melanogaster S2 cells.
  Acta Crystallogr D Biol Crystallogr, 65, 434-439.
PDB code: 3fc0
18182486 K.Chattopadhyay, U.A.Ramagopal, M.Brenowitz, S.G.Nathenson, and S.C.Almo (2008).
Evolution of GITRL immune function: murine GITRL exhibits unique structural and biochemical properties within the TNF superfamily.
  Proc Natl Acad Sci U S A, 105, 635-640.
PDB codes: 2qdn 3b9i
18378892 Z.Zhou, X.Song, A.Berezov, G.Zhang, Y.Li, H.Zhang, R.Murali, B.Li, and M.I.Greene (2008).
Human glucocorticoid-induced TNF receptor ligand regulates its signaling activity through multiple oligomerization states.
  Proc Natl Acad Sci U S A, 105, 5465-5470.  
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.