PDBsum entry 1d2q

Go to PDB code: 
protein links
Cytokine PDB id
Protein chain
134 a.a. *
* Residue conservation analysis
PDB id:
Name: Cytokine
Title: Crystal structure of human trail
Structure: Tnf-related apoptosis inducing ligand. Chain: a, b. Fragment: extra cellular domain. Synonym: trail. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: bacteria. Expression_system_taxid: 2.
Biol. unit: Trimer (from PQS)
2.80Å     R-factor:   0.209     R-free:   0.282
Authors: S.-S.Cha
Key ref:
S.S.Cha et al. (1999). 2.8 A resolution crystal structure of human TRAIL, a cytokine with selective antitumor activity. Immunity, 11, 253-261. PubMed id: 10485660 DOI: 10.1016/S1074-7613(00)80100-4
27-Sep-99     Release date:   11-Feb-00    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P50591  (TNF10_HUMAN) -  Tumor necrosis factor ligand superfamily member 10
281 a.a.
134 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 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: 10.1016/S1074-7613(00)80100-4 Immunity 11:253-261 (1999)
PubMed id: 10485660  
2.8 A resolution crystal structure of human TRAIL, a cytokine with selective antitumor activity.
S.S.Cha, M.S.Kim, Y.H.Choi, B.J.Sung, N.K.Shin, H.C.Shin, Y.C.Sung, B.H.Oh.
TRAIL is a newly identified cytokine belonging to the large tumor necrosis factor (TNF) family. TRAIL is a novel molecule inducing apoptosis in a wide variety of tumor cells but not in normal cells. To help in elucidating its biological roles and designing mutants with improved therapeutic potential, we have determined the crystal structure of human TRAIL. The structure reveals that a unique frame insertion of 12-16 amino acids adopts a salient loop structure penetrating into the receptor-binding site. The loop drastically alters the common receptor-binding surface of the TNF family most likely for the specific recognition of cognate partners. A structure-based mutagenesis study demonstrates a critical role of the insertion loop in the cytotoxic activity of TRAIL.
  Selected figure(s)  
Figure 3.
Figure 3. The AA′′ Loop of TRAIL(A) Interactions of the AA′′ loop along the surface of TRAIL. The residues on the AA′′ and the GH loop are shown in green and khaki, respectively. The cyan dotted lines represent polar interactions. (B) The final 2F[o]-F[c] electron density map contoured at 1σ showing residues 145–155 on the AA′′ loop that interact with the outer β sheet platform. The orientation of the peptide segment is roughly perpendicular to that shown in (A) for clarity. The electron density of this external loop is weaker than that of the central β sheets.
Figure 5.
Figure 5. Sliced View of TRAILThe orientation of TRAIL is the same as in Figure 4. Cavities existing along the central 3-fold axis are in blue. Arrows 1 and 2 indicate the position of Cys-230 and Tyr-183, respectively. The cysteine residue from each subunit should be in the reduced form, since the TRAIL sample for the crystallization contained 1 mM dithiothreitol. The distance between the sulfur atoms (2.6 Å) and the molecular symmetry restriction indicate that these residues cannot form disulfide bonds even in an oxidizing condition. Figure 2 and Figure 3A were produced using the program MOLSCRIPT ( [12]), Figure 3B using the program O ( [16]), and Figure 4 and Figure 5 using the program GRASP ( [15]).
  The above figures are reprinted by permission from Cell Press: Immunity (1999, 11, 253-261) copyright 1999.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20531300 F.Gonzalvez, and A.Ashkenazi (2010).
New insights into apoptosis signaling by Apo2L/TRAIL.
  Oncogene, 29, 4752-4765.  
20506326 L.Martinez-Lostao, F.García-Alvarez, G.Basáñez, E.Alegre-Aguarón, P.Desportes, L.Larrad, J.Naval, M.J.Martínez-Lorenzo, and A.Anel (2010).
Liposome-bound APO2L/TRAIL is an effective treatment in a rabbit model of rheumatoid arthritis.
  Arthritis Rheum, 62, 2272-2282.  
  20360940 M.Mongiat, S.Marastoni, G.Ligresti, E.Lorenzon, M.Schiappacassi, R.Perris, S.Frustaci, and A.Colombatti (2010).
The extracellular matrix glycoprotein elastin microfibril interface located protein 2: a dual role in the tumor microenvironment.
  Neoplasia, 12, 294-304.  
19229339 M.Jeong, Y.S.Kwon, S.H.Park, C.Y.Kim, S.S.Jeun, K.W.Song, Y.Ko, P.D.Robbins, T.R.Billiar, B.M.Kim, and D.W.Seol (2009).
Possible novel therapy for malignant gliomas with secretable trimeric TRAIL.
  PLoS ONE, 4, e4545.  
19836385 P.A.Holoch, and T.S.Griffith (2009).
TNF-related apoptosis-inducing ligand (TRAIL): a new path to anti-cancer therapies.
  Eur J Pharmacol, 625, 63-72.  
19275567 T.S.Griffith, B.Stokes, T.A.Kucaba, J.K.Earel, R.L.VanOosten, E.L.Brincks, and L.A.Norian (2009).
TRAIL gene therapy: from preclinical development to clinical application.
  Curr Gene Ther, 9, 9.  
18219321 C.Adams, K.Totpal, D.Lawrence, S.Marsters, R.Pitti, S.Yee, S.Ross, L.Deforge, H.Koeppen, M.Sagolla, D.Compaan, H.Lowman, S.Hymowitz, and A.Ashkenazi (2008).
Structural and functional analysis of the interaction between the agonistic monoclonal antibody Apomab and the proapoptotic receptor DR5.
  Cell Death Differ, 15, 751-761.
PDB code: 4od2
17891396 M.Ghoneum, N.K.Badr El-Din, E.Noaman, and L.Tolentino (2008).
Saccharomyces cerevisiae, the Baker's Yeast, suppresses the growth of Ehrlich carcinoma-bearing mice.
  Cancer Immunol Immunother, 57, 581-592.  
17917057 M.P.Simons, W.M.Nauseef, and T.S.Griffith (2007).
Neutrophils and TRAIL: insights into BCG immunotherapy for bladder cancer.
  Immunol Res, 39, 79-93.  
16799759 A.Y.Sun, Y.L.Shen, J.C.Yin, H.Zhang, Y.N.Tang, and D.Z.Wei (2006).
Improvement of expression level and bioactivity of soluble tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) by a novel zinc ion feeding strategy.
  Biotechnol Lett, 28, 1215-1219.  
16195699 C.Y.Kim, M.Jeong, H.Mushiake, B.M.Kim, W.B.Kim, J.P.Ko, M.H.Kim, M.Kim, T.H.Kim, P.D.Robbins, T.R.Billiar, and D.W.Seol (2006).
Cancer gene therapy using a novel secretable trimeric TRAIL.
  Gene Ther, 13, 330-338.  
16217763 S.Wolf, D.Mertens, A.Pscherer, P.Schroeter, D.Winkler, H.J.Gröne, C.Hofele, K.Hemminki, R.Kumar, G.Steineck, H.Döhner, S.Stilgenbauer, and P.Lichter (2006).
Ala228 variant of trail receptor 1 affecting the ligand binding site is associated with chronic lymphocytic leukemia, mantle cell lymphoma, prostate cancer, head and neck squamous cell carcinoma and bladder cancer.
  Int J Cancer, 118, 1831-1835.  
15703873 H.C.Shin, and K.H.Cho (2005).
Mutational analysis of human tumor necrosis factor-alpha.
  Biotechnol Lett, 27, 107-112.  
15450251 G.Eissner, W.Kolch, and P.Scheurich (2004).
Ligands working as receptors: reverse signaling by members of the TNF superfamily enhance the plasticity of the immune system.
  Cytokine Growth Factor Rev, 15, 353-366.  
15093829 G.Zhang (2004).
Tumor necrosis factor family ligand-receptor binding.
  Curr Opin Struct Biol, 14, 154-160.  
15511228 S.Y.Park, J.W.Seol, Y.J.Lee, J.H.Cho, H.S.Kang, I.S.Kim, S.H.Park, T.H.Kim, J.H.Yim, M.Kim, T.R.Billiar, and D.W.Seol (2004).
IFN-gamma enhances TRAIL-induced apoptosis through IRF-1.
  Eur J Biochem, 271, 4222-4228.  
12721620 Y.Liu, X.Hong, J.Kappler, L.Jiang, R.Zhang, L.Xu, C.H.Pan, W.E.Martin, R.C.Murphy, H.B.Shu, S.Dai, and G.Zhang (2003).
Ligand-receptor binding revealed by the TNF family member TALL-1.
  Nature, 423, 49-56.
PDB codes: 1oqd 1oqe
12392561 G.H.Nam, and K.Y.Choi (2002).
Association of human tumor necrosis factor-related apoptosis inducing ligand with membrane upon acidification.
  Eur J Biochem, 269, 5280-5287.  
11924906 P.Cappello, F.Novelli, G.Forni, and M.Giovarelli (2002).
Death receptor ligands in tumors.
  J Immunother (1997), 25, 1.  
11733492 S.Ito, K.Wakabayashi, O.Ubukata, S.Hayashi, F.Okada, and T.Hata (2002).
Crystal structure of the extracellular domain of mouse RANK ligand at 2.2-A resolution.
  J Biol Chem, 277, 6631-6636.
PDB code: 1iqa
  11581298 J.Lam, C.A.Nelson, F.P.Ross, S.L.Teitelbaum, and D.H.Fremont (2001).
Crystal structure of the TRANCE/RANKL cytokine reveals determinants of receptor-ligand specificity.
  J Clin Invest, 108, 971-979.
PDB code: 1jtz
11828422 U.Sartorius, I.Schmitz, and P.H.Krammer (2001).
Molecular mechanisms of death-receptor-mediated apoptosis.
  Chembiochem, 2, 20-29.  
11114500 E.Y.Jones (2000).
The tumour necrosis factor receptor family: life or death choices.
  Curr Opin Struct Biol, 10, 644-648.  
10891884 H.T.Idriss, and J.H.Naismith (2000).
TNF alpha and the TNF receptor superfamily: structure-function relationship(s).
  Microsc Res Tech, 50, 184-195.  
10753817 M.C.Deller, and E.Yvonne Jones (2000).
Cell surface receptors.
  Curr Opin Struct Biol, 10, 213-219.  
11039935 M.Yan, L.C.Wang, S.G.Hymowitz, S.Schilbach, J.Lee, A.Goddard, Vos, W.Q.Gao, and V.M.Dixit (2000).
Two-amino acid molecular switch in an epithelial morphogen that regulates binding to two distinct receptors.
  Science, 290, 523-527.  
10651627 S.G.Hymowitz, M.P.O'Connell, M.H.Ultsch, A.Hurst, K.Totpal, A.Ashkenazi, Vos, and R.F.Kelley (2000).
A unique zinc-binding site revealed by a high-resolution X-ray structure of homotrimeric Apo2L/TRAIL.
  Biochemistry, 39, 633-640.
PDB code: 1dg6
10549288 S.G.Hymowitz, H.W.Christinger, G.Fuh, M.Ultsch, M.O'Connell, R.F.Kelley, A.Ashkenazi, and Vos (1999).
Triggering cell death: the crystal structure of Apo2L/TRAIL in a complex with death receptor 5.
  Mol Cell, 4, 563-571.
PDB code: 1d0g
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.