PDBsum entry 1aly

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protein links
Cytokine PDB id
Protein chain
146 a.a. *
Waters ×192
* Residue conservation analysis
PDB id:
Name: Cytokine
Title: Crystal structure of human cd40 ligand
Structure: Cd40 ligand. Chain: a. Fragment: extracellular domain fragment. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Cell_line: pichia pastoris. Tissue: blood. Cell: t-lymphocyte. Cellular_location: membrane. Expressed in: pichia pastoris. Expression_system_taxid: 4922
Biol. unit: Homo-Trimer (from PDB file)
2.00Å     R-factor:   0.223     R-free:   0.295
Authors: M.Karpusas,Y.M.Hsu,D.Thomas
Key ref:
M.Karpusas et al. (1995). 2 A crystal structure of an extracellular fragment of human CD40 ligand. Structure, 3, 1031-1039. PubMed id: 8589998 DOI: 10.1016/S0969-2126(01)00239-8
05-Jun-97     Release date:   17-Sep-97    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P29965  (CD40L_HUMAN) -  CD40 ligand
261 a.a.
146 a.a.
Key:    PfamA domain  PfamB 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/S0969-2126(01)00239-8 Structure 3:1031-1039 (1995)
PubMed id: 8589998  
2 A crystal structure of an extracellular fragment of human CD40 ligand.
M.Karpusas, Y.M.Hsu, J.H.Wang, J.Thompson, S.Lederman, L.Chess, D.Thomas.
BACKGROUND: The CD40 ligand (CD40L) is a member of the tumor necrosis factor (TNF) family of proteins and is transiently expressed on the surface of activated T cells. The binding of CD40L to CD40, which is expressed on the surface of B cells, provides a critical and unique pathway of cellular activation resulting in antibody isotype switching, regulation of apoptosis, and B cell proliferation and differentiation. Naturally occurring mutations of CD40L result in the clinical hyper-IgM syndrome, characterized by an inability to produce immunoglobulins of the IgG, IgA and IgE isotypes. RESULTS: We have determined the crystal structure of a soluble extracellular fragment of human CD40L to 2 A resolution and with an R factor of 21.8%. Although the molecule forms a trimer similar to that found for other members of the TNF family, such as TNF alpha and lymphotoxin-alpha, and exhibits a similar overall fold, there are considerable differences in several loops including those predicted to be involved in CD40 binding. CONCLUSIONS: The structure suggests that most of the hyper-IgM syndrome mutations affect the folding and stability of the molecule rather than the CD40-binding site directly. Despite the fact that the hyper-IgM syndrome mutations are dispersed in the primary sequence, a large fraction of them are clustered in space in the vicinity of a surface loop, close to the predicted CD40-binding site.
  Selected figure(s)  
Figure 1.
Figure 1. Representative regions of the final 2F[o]–F[c] electron density map contoured at 2.5σ. (a) Residues in the vicinity of the CD40 binding site. (b) View of a cluster of three tyrosine and three histidine residues formed in the vicinity of the center of the trimer. The threefold axis is vertical. Figure 1. Representative regions of the final 2F[o]–F[c] electron density map contoured at 2.5σ. (a) Residues in the vicinity of the CD40 binding site. (b) View of a cluster of three tyrosine and three histidine residues formed in the vicinity of the center of the trimer. The threefold axis is vertical.
Figure 3.
Figure 3. Stereo diagram of superimposed Cα backbones of TNFα (green), LTα (blue) and CD40L (red) crystal structures. The view is approximately the same as in Figure 2. Figure 3. Stereo diagram of superimposed Cα backbones of TNFα (green), LTα (blue) and CD40L (red) crystal structures. The view is approximately the same as in [3]Figure 2.
  The above figures are reprinted by permission from Cell Press: Structure (1995, 3, 1031-1039) copyright 1995.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
19841577 A.P.Hsu, T.A.Fleisher, and J.E.Niemela (2009).
Mutation analysis in primary immunodeficiency diseases: case studies.
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19517507 N.Guex, M.C.Peitsch, and T.Schwede (2009).
Automated comparative protein structure modeling with SWISS-MODEL and Swiss-PdbViewer: a historical perspective.
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19426221 R.Elgueta, M.J.Benson, Vries, A.Wasiuk, Y.Guo, and R.J.Noelle (2009).
Molecular mechanism and function of CD40/CD40L engagement in the immune system.
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19444444 Y.C.Tang, M.Thoman, P.J.Linton, and A.Deisseroth (2009).
Use of CD40L immunoconjugates to overcome the defective immune response to vaccines for infections and cancer in the aged.
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17182621 C.Léveillé, M.Bouillon, W.Guo, J.Bolduc, E.Sharif-Askari, Y.El-Fakhry, C.Reyes-Moreno, R.Lapointe, Y.Merhi, J.A.Wilkins, and W.Mourad (2007).
CD40 ligand binds to alpha5beta1 integrin and triggers cell signaling.
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15703873 H.C.Shin, and K.H.Cho (2005).
Mutational analysis of human tumor necrosis factor-alpha.
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15664187 M.L.Narasimhan, M.A.Coca, J.Jin, T.Yamauchi, Y.Ito, T.Kadowaki, K.K.Kim, J.M.Pardo, B.Damsz, P.M.Hasegawa, D.J.Yun, and R.A.Bressan (2005).
Osmotin is a homolog of mammalian adiponectin and controls apoptosis in yeast through a homolog of mammalian adiponectin receptor.
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15711921 S.Bouralexis, D.M.Findlay, and A.Evdokiou (2005).
Death to the bad guys: targeting cancer via Apo2L/TRAIL.
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16370373 S.Fournel, S.Wieckowski, W.Sun, N.Trouche, H.Dumortier, A.Bianco, O.Chaloin, M.Habib, J.C.Peter, P.Schneider, B.Vray, R.E.Toes, R.Offringa, C.J.Melief, J.Hoebeke, and G.Guichard (2005).
C3-symmetric peptide scaffolds are functional mimetics of trimeric CD40L.
  Nat Chem Biol, 1, 377-382.  
16370368 S.G.Hymowitz, and A.Ashkenazi (2005).
Toward small-molecule agonists of TNF receptors.
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16249180 S.Réty, S.Salamitou, I.Garcia-Verdugo, D.J.Hulmes, F.Le Hégarat, R.Chaby, and A.Lewit-Bentley (2005).
The crystal structure of the Bacillus anthracis spore surface protein BclA shows remarkable similarity to mammalian proteins.
  J Biol Chem, 280, 43073-43078.
PDB code: 1wck
15319456 A.Etzioni, and H.D.Ochs (2004).
The hyper IgM syndrome--an evolving story.
  Pediatr Res, 56, 519-525.  
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.
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15093829 G.Zhang (2004).
Tumor necrosis factor family ligand-receptor binding.
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15158769 S.Shankar, and R.K.Srivastava (2004).
Enhancement of therapeutic potential of TRAIL by cancer chemotherapy and irradiation: mechanisms and clinical implications.
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15562003 T.Mori, A.Oguro, T.Ohtsu, and Y.Nakamura (2004).
RNA aptamers selected against the receptor activator of NF-kappaB acquire general affinity to proteins of the tumor necrosis factor receptor family.
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15304006 Y.Fan, Y.Ge, H.Zhu, Y.Wang, B.Yang, Y.Zhuang, H.Ma, and X.Zhang (2004).
Characterization and application of two novel monoclonal antibodies against CD40L: epitope and functional studies on cell membrane CD40L and studies on the origin of soluble serum CD40L.
  Tissue Antigens, 64, 257-263.  
12787558 K.Pfeffer (2003).
Biological functions of tumor necrosis factor cytokines and their receptors.
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14511234 M.I.Vega, L.Santos-Argumedo, S.Huerta-Yepez, R.Luría-Perez, V.Ortiz-Navarrete, A.Isibasi, and C.R.González-Bonilla (2003).
A Salmonella typhi OmpC fusion protein expressing the CD154 Trp140-Ser149 amino acid strand binds CD40 and activates a lymphoma B-cell line.
  Immunology, 110, 206-216.  
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
12189384 A.Ashkenazi (2002).
Targeting death and decoy receptors of the tumour-necrosis factor superfamily.
  Nat Rev Cancer, 2, 420-430.  
11862220 D.A.Oren, Y.Li, Y.Volovik, T.S.Morris, C.Dharia, K.Das, O.Galperina, R.Gentz, and E.Arnold (2002).
Structural basis of BLyS receptor recognition.
  Nat Struct Biol, 9, 288-292.
PDB code: 1kxg
11796220 J.L.Bodmer, P.Schneider, and J.Tschopp (2002).
The molecular architecture of the TNF superfamily.
  Trends Biochem Sci, 27, 19-26.  
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
11562359 B.G.Werneburg, S.J.Zoog, T.T.Dang, M.R.Kehry, and J.J.Crute (2001).
Molecular characterization of CD40 signaling intermediates.
  J Biol Chem, 276, 43334-43342.  
  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
11592086 L.E.Haswell, M.J.Glennie, and A.Al-Shamkhani (2001).
Analysis of the oligomeric requirement for signaling by CD40 using soluble multimeric forms of its ligand, CD154.
  Eur J Immunol, 31, 3094-3100.  
11525169 M.Karpusas, J.Lucci, J.Ferrant, C.Benjamin, F.R.Taylor, K.Strauch, E.Garber, and Y.M.Hsu (2001).
Structure of CD40 ligand in complex with the Fab fragment of a neutralizing humanized antibody.
  Structure, 9, 321-329.
PDB code: 1i9r
11774036 R.K.Srivastava (2001).
TRAIL/Apo-2L: mechanisms and clinical applications in cancer.
  Neoplasia, 3, 535-546.  
10651941 B.Barnhart, G.S.Ford, A.Bhushan, C.Song, and L.R.Covey (2000).
A polymorphic CD40 ligand (CD154) molecule mediates CD40-dependent signalling but interferes with the ability of soluble CD40 to functionally block CD154:CD40 interactions.
  Immunology, 99, 54-61.  
10700427 B.Berner, G.Wolf, K.M.Hummel, G.A.Müller, and M.A.Reuss-Borst (2000).
Increased expression of CD40 ligand (CD154) on CD4+ T cells as a marker of disease activity in rheumatoid arthritis.
  Ann Rheum Dis, 59, 190-195.  
11114500 E.Y.Jones (2000).
The tumour necrosis factor receptor family: life or death choices.
  Curr Opin Struct Biol, 10, 644-648.  
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
10856699 U.Schönbeck, F.Mach, and P.Libby (2000).
CD154 (CD40 ligand).
  Int J Biochem Cell Biol, 32, 687-693.  
9867859 A.E.Morris, R.L.Remmele, R.Klinke, B.M.Macduff, W.C.Fanslow, and R.J.Armitage (1999).
Incorporation of an isoleucine zipper motif enhances the biological activity of soluble CD40L (CD154).
  J Biol Chem, 274, 418-423.  
10366125 E.A.Webster, A.Y.Khakoo, W.J.Mackus, M.Karpusas, D.W.Thomas, A.Davidson, C.L.Christian, and S.Lederman (1999).
An aggressive form of polyarticular arthritis in a man with CD154 mutation (X-linked hyper-IgM syndrome).
  Arthritis Rheum, 42, 1291-1296.  
10559240 E.Garber, L.Su, B.Ehrenfels, M.Karpusas, and Y.M.Hsu (1999).
CD154 variants associated with hyper-IgM syndrome can form oligomers and trigger CD40-mediated signals.
  J Biol Chem, 274, 33545-33550.  
10382675 J.Bajorath (1999).
Identification of the ligand binding site in Fas (CD95) and analysis of Fas-ligand interactions.
  Proteins, 35, 475-482.  
10196221 K.Seyama, W.R.Osborne, and H.D.Ochs (1999).
CD40 ligand mutants responsible for X-linked hyper-IgM syndrome associate with wild type CD40 ligand.
  J Biol Chem, 274, 11310-11320.  
10323442 R.K.Vakkalanka, C.Woo, K.A.Kirou, M.Koshy, D.Berger, and M.K.Crow (1999).
Elevated levels and functional capacity of soluble CD40 ligand in systemic lupus erythematosus sera.
  Arthritis Rheum, 42, 871-881.  
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
11232332 S.M.McWhirter, S.S.Pullen, B.G.Werneburg, M.E.Labadia, R.H.Ingraham, J.J.Crute, M.R.Kehry, and T.Alber (1999).
Structural and biochemical analysis of signal transduction by the TRAF family of adapter proteins.
  Cold Spring Harb Symp Quant Biol, 64, 551-562.  
10411888 S.M.McWhirter, S.S.Pullen, J.M.Holton, J.J.Crute, M.R.Kehry, and T.Alber (1999).
Crystallographic analysis of CD40 recognition and signaling by human TRAF2.
  Proc Natl Acad Sci U S A, 96, 8408-8413.
PDB code: 1qsc
10216319 S.S.Cha, H.C.Shin, K.Y.Choi, and B.H.Oh (1999).
Expression, purification and crystallization of recombinant human TRAIL.
  Acta Crystallogr D Biol Crystallogr, 55, 1101-1104.  
10485660 S.S.Cha, M.S.Kim, Y.H.Choi, B.J.Sung, N.K.Shin, H.C.Shin, Y.C.Sung, and B.H.Oh (1999).
2.8 A resolution crystal structure of human TRAIL, a cytokine with selective antitumor activity.
  Immunity, 11, 253-261.
PDB code: 1d2q
10433725 S.S.Pullen, M.E.Labadia, R.H.Ingraham, S.M.McWhirter, D.S.Everdeen, T.Alber, J.J.Crute, and M.R.Kehry (1999).
High-affinity interactions of tumor necrosis factor receptor-associated factors (TRAFs) and CD40 require TRAF trimerization and CD40 multimerization.
  Biochemistry, 38, 10168-10177.  
9700498 I.D.Campbell (1998).
The modular architecture of leukocyte cell-surface receptors.
  Immunol Rev, 163, 11-18.  
9733755 J.Bajorath (1998).
Detailed comparison of two molecular models of the human CD40 ligand with an x-ray structure and critical assessment of model-based mutagenesis and residue mapping studies.
  J Biol Chem, 273, 24603-24609.  
  9605317 J.Singh, E.Garber, H.Van Vlijmen, M.Karpusas, Y.M.Hsu, Z.Zheng, J.H.Naismith, and D.Thomas (1998).
The role of polar interactions in the molecular recognition of CD40L with its receptor CD40.
  Protein Sci, 7, 1124-1135.  
9512423 L.Shapiro, and P.E.Scherer (1998).
The crystal structure of a complement-1q family protein suggests an evolutionary link to tumor necrosis factor.
  Curr Biol, 8, 335-338.
PDB code: 1c28
9030600 A.Al-Shamkhani, S.Mallett, M.H.Brown, W.James, and A.N.Barclay (1997).
Affinity and kinetics of the interaction between soluble trimeric OX40 ligand, a member of the tumor necrosis factor superfamily, and its receptor OX40 on activated T cells.
  J Biol Chem, 272, 5275-5282.  
9476666 B.Zheng, S.Han, Y.Takahashi, and G.Kelsoe (1997).
Immunosenescence and germinal center reaction.
  Immunol Rev, 160, 63-77.  
9405425 J.R.Orlinick, K.B.Elkon, and M.V.Chao (1997).
Separate domains of the human fas ligand dictate self-association and receptor binding.
  J Biol Chem, 272, 32221-32229.  
9228058 P.Schneider, J.L.Bodmer, N.Holler, C.Mattmann, P.Scuderi, A.Terskikh, M.C.Peitsch, and J.Tschopp (1997).
Characterization of Fas (Apo-1, CD95)-Fas ligand interaction.
  J Biol Chem, 272, 18827-18833.  
  9219031 R.F.Schwabe, S.Hess, J.P.Johnson, and H.Engelmann (1997).
Modulation of soluble CD40 ligand bioactivity with anti-CD40 antibodies.
  Hybridoma, 16, 217-226.  
9336404 S.K.Datta, and S.L.Kalled (1997).
CD40-CD40 ligand interaction in autoimmune disease.
  Arthritis Rheum, 40, 1735-1745.  
8995381 Y.M.Hsu, J.Lucci, L.Su, B.Ehrenfels, E.Garber, and D.Thomas (1997).
Heteromultimeric complexes of CD40 ligand are present on the cell surface of human T lymphocytes.
  J Biol Chem, 272, 911-915.  
8905447 H.J.Gruss (1996).
Molecular, structural, and biological characteristics of the tumor necrosis factor ligand superfamily.
  Int J Clin Lab Res, 26, 143-159.  
  16509032 J.Bajorath, K.Seyama, S.Nonoyama, H.D.Ochs, and A.Aruffo (1996).
Classification of mutations in the human CD40 ligand, gp39, that are associated with X-linked hyper IgM syndrome.
  Protein Sci, 5, 531-534.  
8621492 J.L.Browning, K.Miatkowski, D.A.Griffiths, P.R.Bourdon, C.Hession, C.M.Ambrose, and W.Meier (1996).
Preparation and characterization of soluble recombinant heterotrimeric complexes of human lymphotoxins alpha and beta.
  J Biol Chem, 271, 8618-8626.  
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.