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Hydrolase/hydrolase inhibitor PDB id
1qdu
Jmol
Contents
Protein chains
(+ 0 more) 153 a.a. *
(+ 0 more) 88 a.a. *
Ligands
PHQ-GLU-VAL-ASP-
0QE ×6
Waters ×146
* Residue conservation analysis
PDB id:
1qdu
Name: Hydrolase/hydrolase inhibitor
Title: Crystal structure of the complex of caspase-8 with the tripe ketone inhibitor zevd-dcbmk
Structure: Caspase-8 alpha-chain. Chain: a, c, e, g, i, k. Engineered: yes. Caspase-8 beta-chain. Chain: b, d, f, h, j, l. Engineered: yes. Phq-glu-val-asp-dichloromethylketone inhibitor. Chain: t, u, v, w, x, y. Synonym: z-evd-dcbmk.
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: the peptide was chemically synthesized.
Biol. unit: Hexamer (from PQS)
Resolution:
2.80Å     R-factor:   0.230     R-free:   0.302
Authors: H.Blanchard,M.G.Grutter
Key ref:
H.Blanchard et al. (1999). The three-dimensional structure of caspase-8: an initiator enzyme in apoptosis. Structure, 7, 1125-1133. PubMed id: 10508784 DOI: 10.1016/S0969-2126(99)80179-8
Date:
10-Jul-99     Release date:   10-Jul-00    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q14790  (CASP8_HUMAN) -  Caspase-8
Seq:
Struc: 		479 a.a.
153 a.a.*
Protein chains
Pfam   ArchSchema ?
Q14790  (CASP8_HUMAN) -  Caspase-8
Seq:
Struc: 		479 a.a.
88 a.a.
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: Chains A, B, C, D, E, F, G, H, I, J, K, L: E.C.3.4.22.61  - Caspase-8.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     apoptosis   2 terms 
  Biochemical function     cysteine-type peptidase activity     2 terms  

 

 
DOI no: 10.1016/S0969-2126(99)80179-8 Structure 7:1125-1133 (1999)
PubMed id: 10508784  
 
 
The three-dimensional structure of caspase-8: an initiator enzyme in apoptosis.
H.Blanchard, L.Kodandapani, P.R.Mittl, S.D.Marco, J.F.Krebs, J.C.Wu, K.J.Tomaselli, M.G.Grütter.
 
  ABSTRACT  
 
BACKGROUND: In the initial stages of Fas-mediated apoptosis the cysteine protease caspase-8 is recruited to the cell receptor as a zymogen (procaspase-8) and is incorporated into the death-signalling complex. Procaspase-8 is subsequently activated leading to a cascade of proteolytic events, one of them being the activation of caspase-3, and ultimately resulting in cell destruction. Variations in the substrate specificity of different caspases have been reported. RESULTS: We report here the crystal structure of a complex of the activated human caspase-8 (proteolytic domain) with the irreversible peptidic inhibitor Z-Glu-Val-Asp-dichloromethylketone at 2.8 A resolution. This is the first structure of a representative of the long prodomain initiator caspases and of the group III substrate specificity class. The overall protein architecture resembles the caspase-1 and caspase-3 folds, but shows distinct structural differences in regions forming the active site. In particular, differences observed in subsites S(3), S(4) and the loops involved in inhibitor interactions explain the preference of caspase-8 for substrates with the sequence (Leu/Val)-Glu-X-Asp. CONCLUSIONS: The structural differences could be correlated with the observed substrate specificities of caspase-1, caspase-3 and caspase-8, as determined from kinetic experiments. This information will help us to understand the role of the various caspases in the propagation of the apoptotic signal. The information gained from this investigation should be useful for the design of specific inhibitors.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. Ribbon diagram of the (p18-p12)[2] dimer structure. The p18 and p12 chains are coloured red and green, respectively. The loops around the active site are coloured dark blue and labelled. The inhibitor (Z-EVD), which is covalently bound to the active-site cysteine Cys285, is depicted as a yellow ball-and-stick model. The twofold NCS axis relating the two p18-p12 units is perpendicular to the plane of the paper. (The figure was generated using the program MOLSCRIPT [40].)
 
  The above figure is reprinted by permission from Cell Press: Structure (1999, 7, 1125-1133) copyright 1999.  
  Figure was selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
19851329 N.Keller, M.G.Grütter, and O.Zerbe (2010).
Studies of the molecular mechanism of caspase-8 activation by solution NMR.
  Cell Death Differ, 17, 710-718.  
20012364 V.Heussler, A.Rennenberg, and R.Stanway (2010).
Host cell death induced by the egress of intracellular Plasmodium parasites.
  Apoptosis, 15, 376-385.  
19416807 J.W.Yu, P.D.Jeffrey, and Y.Shi (2009).
Mechanism of procaspase-8 activation by c-FLIPL.
  Proc Natl Acad Sci U S A, 106, 8169-8174.
PDB codes: 3h11 3h13
19278658 N.Keller, J.Mares, O.Zerbe, and M.G.Grütter (2009).
Structural and biochemical studies on procaspase-8: new insights on initiator caspase activation.
  Structure, 17, 438-448.
PDB code: 2k7z
18086677 S.H.Jia, J.Parodo, A.Kapus, O.D.Rotstein, and J.C.Marshall (2008).
Dynamic regulation of neutrophil survival through tyrosine phosphorylation or dephosphorylation of caspase-8.
  J Biol Chem, 283, 5402-5413.  
17052983 J.Dobó, R.Swanson, G.S.Salvesen, S.T.Olson, and P.G.Gettins (2006).
Cytokine response modifier a inhibition of initiator caspases results in covalent complex formation and dissociation of the caspase tetramer.
  J Biol Chem, 281, 38781-38790.  
16619028 S.Cursi, A.Rufini, V.Stagni, I.Condò, V.Matafora, A.Bachi, A.P.Bonifazi, L.Coppola, G.Superti-Furga, R.Testi, and D.Barilà (2006).
Src kinase phosphorylates Caspase-8 on Tyr380: a novel mechanism of apoptosis suppression.
  EMBO J, 25, 1895-1905.  
16003388 S.Misaghi, G.A.Korbel, B.Kessler, E.Spooner, and H.L.Ploegh (2006).
z-VAD-fmk inhibits peptide:N-glycanase and may result in ER stress.
  Cell Death Differ, 13, 163-165.  
16200200 I.N.Lavrik, A.Golks, and P.H.Krammer (2005).
Caspases: pharmacological manipulation of cell death.
  J Clin Invest, 115, 2665-2672.  
16212486 N.Yan, and Y.Shi (2005).
Mechanisms of apoptosis through structural biology.
  Annu Rev Cell Dev Biol, 21, 35-56.  
15828006 S.Piana, Z.Taylor, and U.Rothlisberger (2005).
Folding pathways for initiator and effector procaspases from computer simulations.
  Proteins, 59, 765-772.  
15520809 S.J.Riedl, and Y.Shi (2004).
Molecular mechanisms of caspase regulation during apoptosis.
  Nat Rev Mol Cell Biol, 5, 897-907.  
15189137 X.Jiang, and X.Wang (2004).
Cytochrome C-mediated apoptosis.
  Annu Rev Biochem, 73, 87.  
12920126 A.Schweizer, C.Briand, and M.G.Grutter (2003).
Crystal structure of caspase-2, apical initiator of the intrinsic apoptotic pathway.
  J Biol Chem, 278, 42441-42447.
PDB code: 1pyo
12949717 H.S.Kim, J.W.Lee, Y.H.Soung, W.S.Park, S.Y.Kim, J.H.Lee, J.Y.Park, Y.G.Cho, C.J.Kim, S.W.Jeong, S.W.Nam, S.H.Kim, J.Y.Lee, N.J.Yoo, and S.H.Lee (2003).
Inactivating mutations of caspase-8 gene in colorectal carcinomas.
  Gastroenterology, 125, 708-715.  
12620239 K.M.Boatright, M.Renatus, F.L.Scott, S.Sperandio, H.Shin, I.M.Pedersen, J.E.Ricci, W.A.Edris, D.P.Sutherlin, D.R.Green, and G.S.Salvesen (2003).
A unified model for apical caspase activation.
  Mol Cell, 11, 529-541.  
12482880 M.Bando, M.Hasegawa, Y.Tsuboi, Y.Miyake, M.Shiina, M.Ito, H.Handa, K.Nagai, and T.Kataoka (2003).
The mycotoxin penicillic acid inhibits Fas ligand-induced apoptosis by blocking self-processing of caspase-8 in death-inducing signaling complex.
  J Biol Chem, 278, 5786-5793.  
12732719 S.Stoven, N.Silverman, A.Junell, M.Hedengren-Olcott, D.Erturk, Y.Engstrom, T.Maniatis, and D.Hultmark (2003).
Caspase-mediated processing of the Drosophila NF-kappaB factor Relish.
  Proc Natl Acad Sci U S A, 100, 5991-5996.  
12065591 A.Benchoua, C.Couriaud, C.Guégan, L.Tartier, P.Couvert, G.Friocourt, J.Chelly, J.Ménissier-de Murcia, and B.Onténiente (2002).
Active caspase-8 translocates into the nucleus of apoptotic cells to inactivate poly(ADP-ribose) polymerase-2.
  J Biol Chem, 277, 34217-34222.  
12197899 A.Ueki, Y.Isozaki, A.Tomokuni, T.Hatayama, H.Ueki, M.Kusaka, M.Shiwa, H.Arikuni, T.Takeshita, and K.Morimoto (2002).
Intramolecular epitope spreading among anti-caspase-8 autoantibodies in patients with silicosis, systemic sclerosis and systemic lupus erythematosus, as well as in healthy individuals.
  Clin Exp Immunol, 129, 556-561.  
12215447 O.Micheau, M.Thome, P.Schneider, N.Holler, J.Tschopp, D.W.Nicholson, C.Briand, and M.G.Grütter (2002).
The long form of FLIP is an activator of caspase-8 at the Fas death-inducing signaling complex.
  J Biol Chem, 277, 45162-45171.  
11931755 Y.Shi (2002).
Mechanisms of caspase activation and inhibition during apoptosis.
  Mol Cell, 9, 459-470.  
11425640 J.C.Reed (2001).
Apoptosis-regulating proteins as targets for drug discovery.
  Trends Mol Med, 7, 314-319.  
11257230 J.Chai, E.Shiozaki, S.M.Srinivasula, Q.Wu, P.Datta, E.S.Alnemri, Y.Shi, and P.Dataa (2001).
Structural basis of caspase-7 inhibition by XIAP.
  Cell, 104, 769-780.
PDB code: 1i51
11701129 J.Chai, Q.Wu, E.Shiozaki, S.M.Srinivasula, E.S.Alnemri, and Y.Shi (2001).
Crystal structure of a procaspase-7 zymogen: mechanisms of activation and substrate binding.
  Cell, 107, 399-407.
PDB codes: 1k86 1k88
11325591 J.Rotonda, M.Garcia-Calvo, H.G.Bull, W.M.Geissler, B.M.McKeever, C.A.Willoughby, N.A.Thornberry, and J.W.Becker (2001).
The three-dimensional structure of human granzyme B compared to caspase-3, key mediators of cell death with cleavage specificity for aspartic acid in P1.
  Chem Biol, 8, 357-368.
PDB code: 1iau
11257232 S.J.Riedl, M.Renatus, R.Schwarzenbacher, Q.Zhou, C.Sun, S.W.Fesik, R.C.Liddington, and G.S.Salvesen (2001).
Structural basis for the inhibition of caspase-3 by XIAP.
  Cell, 104, 791-800.
PDB code: 1i3o
11752425 S.J.Riedl, P.Fuentes-Prior, M.Renatus, N.Kairies, S.Krapp, R.Huber, G.S.Salvesen, and W.Bode (2001).
Structural basis for the activation of human procaspase-7.
  Proc Natl Acad Sci U S A, 98, 14790-14795.
PDB code: 1gqf
11828422 U.Sartorius, I.Schmitz, and P.H.Krammer (2001).
Molecular mechanisms of death-receptor-mediated apoptosis.
  Chembiochem, 2, 20-29.  
  11257231 Y.Huang, Y.C.Park, R.L.Rich, D.Segal, D.G.Myszka, and H.Wu (2001).
Structural basis of caspase inhibition by XIAP: differential roles of the linker versus the BIR domain.
  Cell, 104, 781-790.
PDB code: 1i4o
11114500 E.Y.Jones (2000).
The tumour necrosis factor receptor family: life or death choices.
  Curr Opin Struct Biol, 10, 644-648.  
  11102794 J.C.Reed, and K.J.Tomaselli (2000).
Drug discovery opportunities from apoptosis research.
  Curr Opin Biotechnol, 11, 586-592.  
11114501 M.G.Grütter (2000).
Caspases: key players in programmed cell death.
  Curr Opin Struct Biol, 10, 649-655.  
  10903953 M.Renatus, Q.Zhou, H.R.Stennicke, S.J.Snipas, D.Turk, L.A.Bankston, R.C.Liddington, and G.S.Salvesen (2000).
Crystal structure of the apoptotic suppressor CrmA in its cleaved form.
  Structure, 8, 789-797.
PDB code: 1f0c
11057900 S.W.Fesik (2000).
Insights into programmed cell death through structural biology.
  Cell, 103, 273-282.  
10873833 Y.Wei, T.Fox, S.P.Chambers, J.Sintchak, J.T.Coll, J.M.Golec, L.Swenson, K.P.Wilson, and P.S.Charifson (2000).
The structures of caspases-1, -3, -7 and -8 reveal the basis for substrate and inhibitor selectivity.
  Chem Biol, 7, 423-432.
PDB code: 1f1j
  10545333 G.S.Salvesen (1999).
Caspase 8: igniting the death machine.
  Structure, 7, R225-R229.  
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.