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Apoptosis, hydrolase/hydrolase inhibitor PDB id
1f1j
Jmol
Contents
Protein chains
230 a.a. *
Ligands
ACE-ASP-GLU-VAL-
ASA ×2
SO4 ×2
Waters ×397
* Residue conservation analysis
PDB id:
1f1j
Name: Apoptosis, hydrolase/hydrolase inhibitor
Title: Crystal structure of caspase-7 in complex with acetyl-asp-gl cho
Structure: Caspase-7 protease. Chain: a, b. Fragment: p20/p10 catalytic domain. Engineered: yes. Ace-asp-glu-val-asp-cho. Chain: c, d. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: this sequence was chemically synthesized
Biol. unit: Tetramer (from PQS)
Resolution:
2.35Å     R-factor:   0.185     R-free:   0.263
Authors: Y.Wei,P.S.Charifson
Key ref:
Y.Wei et al. (2000). The structures of caspases-1, -3, -7 and -8 reveal the basis for substrate and inhibitor selectivity. Chem Biol, 7, 423-432. PubMed id: 10873833 DOI: 10.1016/S1074-5521(00)00123-X
Date:
19-May-00     Release date:   23-May-01    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P55210  (CASP7_HUMAN) -  Caspase-7
Seq:
Struc: 		303 a.a.
230 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.3.4.22.60  - Caspase-7.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     soluble fraction   7 terms 
  Biological process     aging   12 terms 
  Biochemical function     protein binding     6 terms  

 

 
DOI no: 10.1016/S1074-5521(00)00123-X Chem Biol 7:423-432 (2000)
PubMed id: 10873833  
 
 
The structures of caspases-1, -3, -7 and -8 reveal the basis for substrate and inhibitor selectivity.
Y.Wei, T.Fox, S.P.Chambers, J.Sintchak, J.T.Coll, J.M.Golec, L.Swenson, K.P.Wilson, P.S.Charifson.
 
  ABSTRACT  
 
BACKGROUND: Peptide inhibitors of caspases have helped define the role of these cysteine proteases in biology. Structural and biochemical characterization of the caspase enzymes may contribute to the development of new drugs for the treatment of caspase-mediated inflammation and apoptosis. RESULTS: The crystal structure of the previously unpublished caspase-7 (Csp7; 2.35 A) bound to the reversible tetrapeptide aldehyde inhibitor acetyl-Asp-Glu-Val-Asp-CHO is compared with crystal structures of caspases-1 (2.3 A), -3 (2.2 A), and -8 (2.65 A) bound to the same inhibitor. Csp7 is a close homolog of caspase-3 (Csp3), and these two caspases possess some quarternary structural characteristics that support their unique role among the caspase family. However, although Csp3 and Csp7 are quite similar overall, they were found to have a significantly different substitution pattern of amino acids in and around the S4-binding site. CONCLUSIONS: These structures span all three caspase subgroups, and provide a basis for inferring substrate and inhibitor binding, as well as selectivity for the entire caspase family. This information will influence the design of selective caspase inhibitors to further elucidate the role of caspases in biology and hopefully lead to the design of therapeutic agents to treat caspase-mediated diseases, such as rheumatoid arthritis, certain neurogenerative diseases and stroke.
 
  Selected figure(s)  
 
Figure 3.
Figure 3. Sequence alignment of Csp1, Csp3, Csp7 and Csp8. The alignment was heavily biased upon the superposition of conserved secondary structural elements and active site residues of Csp1, Csp3, Csp7 and Csp8. The alignment was performed with the MVP program [47] and then adjusted manually. Boxed residues denote direct or water-mediated interactions with Ac-DEVD-CHO as shown in Figure 4. Amino acid color coding is as follows: green, hydrophobic; purple, basic; orange, acidic; yellow, histidine; black, proline, glycine; gray, serine and threonine; pink, asparagine and/or glutamine. 		Figure 4.
Figure 4. Schematic showing hydrogen bonding and van der Waals interactions of covalently bound Ac-DEVD–thiohemiacetal with binding-site residues of (a) Csp1, (b) Csp3, (c) Csp7 and (d) Csp8. Wat, water molecule.
 
  The above figures are reprinted by permission from Cell Press: Chem Biol (2000, 7, 423-432) copyright 2000.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20942802 D.Boucher, V.Blais, M.Drag, and J.B.Denault (2011).
Molecular determinants involved in activation of caspase 7.
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19782763 M.Lamkanfi, and T.D.Kanneganti (2010).
Caspase-7: a protease involved in apoptosis and inflammation.
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20101263 M.Luo, Z.Lu, H.Sun, K.Yuan, Q.Zhang, S.Meng, F.Wang, H.Guo, X.Ju, Y.Liu, T.Ye, Z.Lu, and Z.Zhai (2010).
Nuclear entry of active caspase-3 is facilitated by its p3-recognition-based specific cleavage activity.
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19759058 D.Demon, P.Van Damme, T.Vanden Berghe, A.Deceuninck, J.Van Durme, J.Verspurten, K.Helsens, F.Impens, M.Wejda, J.Schymkowitz, F.Rousseau, A.Madder, J.Vandekerckhove, W.Declercq, K.Gevaert, and P.Vandenabeele (2009).
Proteome-wide substrate analysis indicates substrate exclusion as a mechanism to generate caspase-7 versus caspase-3 specificity.
  Mol Cell Proteomics, 8, 2700-2714.  
19892984 D.W.Wolan, J.A.Zorn, D.C.Gray, and J.A.Wells (2009).
Small-molecule activators of a proenzyme.
  Science, 326, 853-858.  
19581639 J.A.Hardy, and J.A.Wells (2009).
Dissecting an allosteric switch in caspase-7 using chemical and mutational probes.
  J Biol Chem, 284, 26063-26069.  
19655253 J.Agniswamy, B.Fang, and I.T.Weber (2009).
Conformational similarity in the activation of caspase-3 and -7 revealed by the unliganded and inhibited structures of caspase-7.
  Apoptosis, 14, 1135-1144.
PDB codes: 3ibc 3ibf
20735596 K.Sakamaki, and Y.Satou (2009).
Caspases: evolutionary aspects of their functions in vertebrates.
  J Fish Biol, 74, 727-753.  
19740426 P.Weber, P.Wang, S.Maddens, P.S.h.Wang, R.Wu, M.Miksa, W.Dong, M.Mortimore, J.M.Golec, and P.Charlton (2009).
VX-166: a novel potent small molecule caspase inhibitor as a potential therapy for sepsis.
  Crit Care, 13, R146.  
19694615 R.Baumgartner, G.Meder, C.Briand, A.Decock, A.D'arcy, U.Hassiepen, R.Morse, and M.Renatus (2009).
The crystal structure of caspase-6, a selective effector of axonal degeneration.
  Biochem J, 423, 429-439.
PDB code: 2wdp
19530232 W.A.Witkowski, and J.A.Hardy (2009).
L2' loop is critical for caspase-7 active site formation.
  Protein Sci, 18, 1459-1468.
PDB code: 3h1p
18026127 A.Muscella, N.Calabriso, F.P.Fanizzi, S.A.De Pascali, L.Urso, A.Ciccarese, D.Migoni, and S.Marsigliante (2008).
[Pt(O,O'-acac)(gamma-acac)(DMS)], a new Pt compound exerting fast cytotoxicity in MCF-7 breast cancer cells via the mitochondrial apoptotic pathway.
  Br J Pharmacol, 153, 34-49.  
18700819 C.Li, S.J.Barker, D.G.Gilchrist, J.E.Lincoln, and W.A.Cowling (2008).
Leptosphaeria maculans elicits apoptosis coincident with leaf lesion formation and hyphal advance in Brassica napus.
  Mol Plant Microbe Interact, 21, 1143-1153.  
18780184 G.Fu, A.A.Chumanevich, J.Agniswamy, B.Fang, R.W.Harrison, and I.T.Weber (2008).
Structural basis for executioner caspase recognition of P5 position in substrates.
  Apoptosis, 13, 1291-1302.
PDB codes: 3edq 3edr
17594508 A.Yoshimori, J.Sakai, S.Sunaga, T.Kobayashi, S.Takahashi, N.Okita, R.Takasawa, and S.Tanuma (2007).
Structural and functional definition of the specificity of a novel caspase-3 inhibitor, Ac-DNLD-CHO.
  BMC Pharmacol, 7, 8.  
17088257 B.Korkmaz, E.Hajjar, T.Kalupov, N.Reuter, M.Brillard-Bourdet, T.Moreau, L.Juliano, and F.Gauthier (2007).
Influence of charge distribution at the active site surface on the substrate specificity of human neutrophil protease 3 and elastase. A kinetic and molecular modeling analysis.
  J Biol Chem, 282, 1989-1997.  
17697120 J.Agniswamy, B.Fang, and I.T.Weber (2007).
Plasticity of S2-S4 specificity pockets of executioner caspase-7 revealed by structural and kinetic analysis.
  FEBS J, 274, 4752-4765.
PDB codes: 2ql5 2ql7 2ql9 2qlb 2qlf 2qlj
17181147 A.J.Henzing, H.Dodson, J.M.Reid, S.H.Kaufmann, R.L.Baxter, and W.C.Earnshaw (2006).
Synthesis of novel caspase inhibitors for characterization of the active caspase proteome in vitro and in vivo.
  J Med Chem, 49, 7636-7645.  
16352606 D.Twiddy, G.M.Cohen, M.Macfarlane, and K.Cain (2006).
Caspase-7 is directly activated by the approximately 700-kDa apoptosome complex and is released as a stable XIAP-caspase-7 approximately 200-kDa complex.
  J Biol Chem, 281, 3876-3888.  
16630893 Q.Yin, H.H.Park, J.Y.Chung, S.C.Lin, Y.C.Lo, L.S.da Graca, X.Jiang, and H.Wu (2006).
Caspase-9 holoenzyme is a specific and optimal procaspase-3 processing machine.
  Mol Cell, 22, 259-268.  
16774469 S.F.Larner, R.L.Hayes, and K.K.Wang (2006).
Unfolded protein response after neurotrauma.
  J Neurotrauma, 23, 807-829.  
16200200 I.N.Lavrik, A.Golks, and P.H.Krammer (2005).
Caspases: pharmacological manipulation of cell death.
  J Clin Invest, 115, 2665-2672.  
15937284 M.S.Willis, J.K.Hogan, P.Prabhakar, X.Liu, K.Tsai, Y.Wei, and T.Fox (2005).
Investigation of protein refolding using a fractional factorial screen: a study of reagent effects and interactions.
  Protein Sci, 14, 1818-1826.  
16212486 N.Yan, and Y.Shi (2005).
Mechanisms of apoptosis through structural biology.
  Annu Rev Cell Dev Biol, 21, 35-56.  
15953353 S.F.Larner, D.M.McKinsey, R.L.Hayes, and K.K.W Wang (2005).
Caspase 7: increased expression and activation after traumatic brain injury in rats.
  J Neurochem, 94, 97.  
16227597 S.Kamada, U.Kikkawa, Y.Tsujimoto, and T.Hunter (2005).
A-kinase-anchoring protein 95 functions as a potential carrier for the nuclear translocation of active caspase 3 through an enzyme-substrate-like association.
  Mol Cell Biol, 25, 9469-9477.  
15569692 S.Kamada, U.Kikkawa, Y.Tsujimoto, and T.Hunter (2005).
Nuclear translocation of caspase-3 is dependent on its proteolytic activation and recognition of a substrate-like protein(s).
  J Biol Chem, 280, 857-860.  
15828006 S.Piana, Z.Taylor, and U.Rothlisberger (2005).
Folding pathways for initiator and effector procaspases from computer simulations.
  Proteins, 59, 765-772.  
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
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
15544161 R.Ran, G.Zhou, A.Lu, L.Zhang, Y.Tang, A.C.Rigby, and F.R.Sharp (2004).
Hsp70 mutant proteins modulate additional apoptotic pathways and improve cell survival.
  Cell Stress Chaperones, 9, 229-242.  
15520809 S.J.Riedl, and Y.Shi (2004).
Molecular mechanisms of caspase regulation during apoptosis.
  Nat Rev Mol Cell Biol, 5, 897-907.  
15146491 S.Piana, and U.Rothlisberger (2004).
Molecular dynamics simulations of structural changes during procaspase 3 activation.
  Proteins, 55, 932-941.  
15273300 Y.Shi (2004).
Caspase activation, inhibition, and reactivation: a mechanistic view.
  Protein Sci, 13, 1979-1987.  
15210107 Y.Shi (2004).
Caspase activation: revisiting the induced proximity model.
  Cell, 117, 855-858.  
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
12917395 C.A.Guimarães, M.Benchimol, G.P.Amarante-Mendes, and R.Linden (2003).
Alternative programs of cell death in developing retinal tissue.
  J Biol Chem, 278, 41938-41946.  
12833566 C.Z.Ni, C.Li, J.C.Wu, A.P.Spada, and K.R.Ely (2003).
Conformational restrictions in the active site of unliganded human caspase-3.
  J Mol Recognit, 16, 121-124.
PDB code: 1qx3
12824163 J.B.Denault, and G.S.Salvesen (2003).
Human caspase-7 activity and regulation by its N-terminal peptide.
  J Biol Chem, 278, 34042-34050.  
  14573360 J.J.Alam (2003).
Apoptosis: target for novel drugs.
  Trends Biotechnol, 21, 479-483.  
14644197 K.M.Boatright, and G.S.Salvesen (2003).
Mechanisms of caspase activation.
  Curr Opin Cell Biol, 15, 725-731.  
12833545 M.Sulpizi, A.Laio, J.VandeVondele, A.Cattaneo, U.Rothlisberger, and P.Carloni (2003).
Reaction mechanism of caspases: insights from QM/MM Car-Parrinello simulations.
  Proteins, 52, 212-224.  
12668429 M.Sulpizi, U.Rothlisberger, and P.Carloni (2003).
Molecular dynamics studies of caspase-3.
  Biophys J, 84, 2207-2215.  
12970077 W.Yang, J.Guastella, J.C.Huang, Y.Wang, L.Zhang, D.Xue, M.Tran, R.Woodward, S.Kasibhatla, B.Tseng, J.Drewe, and S.X.Cai (2003).
MX1013, a dipeptide caspase inhibitor with potent in vivo antiapoptotic activity.
  Br J Pharmacol, 140, 402-412.  
12450324 J.Salgado, A.J.García-Sáez, G.Malet, I.Mingarro, and E.Pérez-Payá (2002).
Peptides in apoptosis research.
  J Pept Sci, 8, 543-560.  
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.  
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
11734640 M.Renatus, H.R.Stennicke, F.L.Scott, R.C.Liddington, and G.S.Salvesen (2001).
Dimer formation drives the activation of the cell death protease caspase 9.
  Proc Natl Acad Sci U S A, 98, 14250-14255.
PDB code: 1jxq
11470611 P.R.Caron, M.D.Mullican, R.D.Mashal, K.P.Wilson, M.S.Su, and M.A.Murcko (2001).
Chemogenomic approaches to drug discovery.
  Curr Opin Chem Biol, 5, 464-470.  
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
  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
11209755 E.Estébanez-Perpiña, P.Fuentes-Prior, D.Belorgey, M.Braun, R.Kiefersauer, K.Maskos, R.Huber, H.Rubin, and W.Bode (2000).
Crystal structure of the caspase activator human granzyme B, a proteinase highly specific for an Asp-P1 residue.
  Biol Chem, 381, 1203-1214.
PDB code: 1fq3
11114501 M.G.Grütter (2000).
Caspases: key players in programmed cell death.
  Curr Opin Struct Biol, 10, 649-655.  
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.