PDBsum entry 1qtn

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Hydrolase/hydrolase inhibitor PDB id
Protein chains
152 a.a. *
90 a.a. *
DTD ×2
Waters ×332
* Residue conservation analysis
PDB id:
Name: Hydrolase/hydrolase inhibitor
Title: Crystal structure of the complex of caspase-8 with the tetra inhibitor ace-ietd-aldehyde
Structure: Caspase-8. Chain: a. Fragment: p18 fragment. Engineered: yes. Caspase-8. Chain: b. Fragment: p11 fragment. Engineered: yes. Acetyl-ile-glu-thr-asp-aldehyde.
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: chemically synthesized
Biol. unit: Hexamer (from PDB file)
1.20Å     R-factor:   0.166     R-free:   0.188
Authors: W.Watt,K.D.Watenpaugh
Key ref:
W.Watt et al. (1999). The atomic-resolution structure of human caspase-8, a key activator of apoptosis. Structure, 7, 1135-1143. PubMed id: 10508785 DOI: 10.1016/S0969-2126(99)80180-4
28-Jun-99     Release date:   20-Sep-00    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
Q14790  (CASP8_HUMAN) -  Caspase-8
479 a.a.
152 a.a.
Protein chain
Pfam   ArchSchema ?
Q14790  (CASP8_HUMAN) -  Caspase-8
479 a.a.
90 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chains A, B: E.C.  - Caspase-8.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     apoptotic process   2 terms 
  Biochemical function     cysteine-type peptidase activity     2 terms  


DOI no: 10.1016/S0969-2126(99)80180-4 Structure 7:1135-1143 (1999)
PubMed id: 10508785  
The atomic-resolution structure of human caspase-8, a key activator of apoptosis.
W.Watt, K.A.Koeplinger, A.M.Mildner, R.L.Heinrikson, A.G.Tomasselli, K.D.Watenpaugh.
BACKGROUND: Caspases are a family of cysteine proteases that have important intracellular roles in inflammation and apoptosis. Caspase-8 activates downstream caspases which are unable to carry out autocatalytic processing and activation. Caspase-8 is designated as an initiator caspase and is believed to sit at the apex of the Fas- or TNF-mediated apoptotic cascade. In view of this role, the enzyme is an attractive target for the design of inhibitors aimed at blocking the undesirable cell death associated with a range of degenerative disorders. RESULTS: The structure of recombinant human caspase-8, covalently modified with the inhibitor acetyl-Ile-Glu-Thr-Asp-aldehyde, has been determined by X-ray crystallography to 1.2 A resolution. The asymmetric unit contains the p18-p11 heterodimer; the biologically important molecule contains two dimers. The overall fold is very similar to that of caspase-1 and caspase-3, but significant differences exist in the substrate-binding region. The structure answers questions about the enzyme-inhibitor complex that could not be explained from earlier caspase structures solved at lower resolution. CONCLUSIONS: The catalytic triad in caspase-8 comprises Cys360, His317 and the backbone carbonyl oxygen atom of Arg258, which points towards the Nepsilon atom of His317. The oxygen atom attached to the tetrahedral carbon in the thiohemiacetal group of the inhibitor is hydrogen bonded to Ndelta of His317, and is not in a region characteristic of a classical 'oxyanion hole'. The N-acetyl group of the inhibitor is in the trans configuration. The caspase-8-inhibitor structure provides the basis for understanding structure/function relationships in this important initiator of the proteolytic cascade that leads to programmed cell death.
  Selected figure(s)  
Figure 4.
Figure 4. Molecular surface representation of (a) caspase-8 and (b) caspase-3 generated using the program GRASP [37] and viewed down the twofold axis. Areas of negative and positive electrostatic potential are shown in red and blue, respectively. The surface is viewed approximately parallel to the twofold axis. The central cavities are outlined in black and the tetrapeptide inhibitors and dithiane-diol molecules are shown as stick models. (c) Close-up view of the electron density of the dithiane-diol molecule located in the central cavity of caspase-8.
  The above figure is reprinted by permission from Cell Press: Structure (1999, 7, 1135-1143) copyright 1999.  
  Figure was selected by an automated process.  

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.  
19918833 P.Reszka, R.Schulz, K.Methling, M.Lalk, and P.J.Bednarski (2010).
Synthesis, enzymatic evaluation, and docking studies of fluorogenic caspase 8 tetrapeptide substrates.
  ChemMedChem, 5, 103-117.  
20005201 R.Sengupta, T.R.Billiar, V.E.Kagan, and D.A.Stoyanovsky (2010).
Nitric oxide and thioredoxin type 1 modulate the activity of caspase 8 in HepG2 cells.
  Biochem Biophys Res Commun, 391, 1127-1130.  
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.  
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.  
16870616 Y.S.Hsiao, G.Jogl, and L.Tong (2006).
Crystal structures of murine carnitine acetyltransferase in ternary complexes with its substrates.
  J Biol Chem, 281, 28480-28487.
PDB codes: 2h3p 2h3u 2h3w
16212486 N.Yan, and Y.Shi (2005).
Mechanisms of apoptosis through structural biology.
  Annu Rev Cell Dev Biol, 21, 35-56.  
14645217 C.M.Forsyth, D.Lemongello, D.J.LaCount, P.D.Friesen, and A.J.Fisher (2004).
Crystal structure of an invertebrate caspase.
  J Biol Chem, 279, 7001-7008.
PDB code: 1m72
15089039 H.J.Chae, H.R.Kim, J.Bae, S.U.Chae, K.C.Ha, and S.W.Chae (2004).
Signal transduction of the protective effect of insulin like growth factor-1 on adriamycin-induced apoptosis in cardiac muscle cells.
  Arch Pharm Res, 27, 324-333.  
15314233 J.A.Hardy, J.Lam, J.T.Nguyen, T.O'Brien, and J.A.Wells (2004).
Discovery of an allosteric site in the caspases.
  Proc Natl Acad Sci U S A, 101, 12461-12466.
PDB codes: 1shj 1shl
15296730 M.J.Romanowski, J.M.Scheer, T.O'Brien, and R.S.McDowell (2004).
Crystal structures of a ligand-free and malonate-bound human caspase-1: implications for the mechanism of substrate binding.
  Structure, 12, 1361-1371.
PDB codes: 1sc1 1sc3 1sc4
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
12912912 D.W.Chang, Z.Xing, V.L.Capacio, M.E.Peter, and X.Yang (2003).
Interdimer processing mechanism of procaspase-8 activation.
  EMBO J, 22, 4132-4142.  
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.  
12761214 X.Tao, and L.Tong (2003).
Crystal structure of human DJ-1, a protein associated with early onset Parkinson's disease.
  J Biol Chem, 278, 31372-31379.
PDB codes: 1pdv 1pdw 1pe0
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.  
11741952 Y.T.Zhou, U.J.Soh, X.Shang, G.R.Guy, and B.C.Low (2002).
The BNIP-2 and Cdc42GAP homology/Sec14p-like domain of BNIP-Salpha is a novel apoptosis-inducing sequence.
  J Biol Chem, 277, 7483-7492.  
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.