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PDBsum entry 1cp3
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Hydrolase/hydrolase inhibitor PDB id
1cp3

 

 

 

 

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Contents
Protein chains
232 a.a. *
Ligands
ACE-ASP-VAL-ALA-
ASP-CF0 ×2
Waters ×346
* Residue conservation analysis
PDB id:
1cp3
Name: Hydrolase/hydrolase inhibitor
Title: Crystal structure of the complex of apopain with the tetrapeptide inhibitor ace-dvad-fmc
Structure: Apopain. Chain: a, b. Synonym: caspase-3, cpp32, yama. Engineered: yes. Acetyl-asp-val-ala-asp-fluoromethylketone. Chain: c, d. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes
Biol. unit: Tetramer (from PDB file)
Resolution:
2.30Å     R-factor:   0.188     R-free:   0.284
Authors: P.R.E.Mittl,S.Dimarco,M.G.Gruetter
Key ref:
P.R.Mittl et al. (1997). Structure of recombinant human CPP32 in complex with the tetrapeptide acetyl-Asp-Val-Ala-Asp fluoromethyl ketone. J Biol Chem, 272, 6539-6547. PubMed id: 9045680 DOI: 10.1074/jbc.272.10.6539
Date:
12-Dec-96     Release date:   24-Dec-97    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P42574  (CASP3_HUMAN) -  Caspase-3 from Homo sapiens
Seq:
Struc: 		277 a.a.
232 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.3.4.22.56  - caspase-3.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

 

 
DOI no: 10.1074/jbc.272.10.6539 J Biol Chem 272:6539-6547 (1997)
PubMed id: 9045680  
 
 
Structure of recombinant human CPP32 in complex with the tetrapeptide acetyl-Asp-Val-Ala-Asp fluoromethyl ketone.
P.R.Mittl, S.Di Marco, J.F.Krebs, X.Bai, D.S.Karanewsky, J.P.Priestle, K.J.Tomaselli, M.G.Grütter.
 
  ABSTRACT  
 
The cysteine protease CPP32 has been expressed in a soluble form in Escherichia coli and purified to >95% purity. The three-dimensional structure of human CPP32 in complex with the irreversible tetrapeptide inhibitor acetyl-Asp-Val-Ala-Asp fluoromethyl ketone was determined by x-ray crystallography at a resolution of 2.3 A. The asymmetric unit contains a (p17/p12)2 tetramer, in agreement with the tetrameric structure of the protein in solution as determined by dynamic light scattering and size exclusion chromatography. The overall topology of CPP32 is very similar to that of interleukin-1beta-converting enzyme (ICE); however, differences exist at the N terminus of the p17 subunit, where the first helix found in ICE is missing in CPP32. A deletion/insertion pattern is responsible for the striking differences observed in the loops around the active site. In addition, the P1 carbonyl of the ketone inhibitor is pointing into the oxyanion hole and forms a hydrogen bond with the peptidic nitrogen of Gly-122, resulting in a different state compared with the tetrahedral intermediate observed in the structure of ICE and CPP32 in complex with an aldehyde inhibitor. The topology of the interface formed by the two p17/p12 heterodimers of CPP32 is different from that of ICE. This results in different orientations of CPP32 heterodimers compared with ICE heterodimers, which could affect substrate recognition. This structural information will be invaluable for the design of small synthetic inhibitors of CPP32 as well as for the design of CPP32 mutants.
 
  Selected figure(s)  
 
Figure 7.
Fig. 7. Molecular surface of the CPP32 tetramer generated by GRASP (45). The molecule is seen parallel to the 2-fold axis. The surface is colored according to its electrostatic potential. Red and blue areas represent negative and positive charge density, respectively. Two Ac-DVAD-fmk molecules (colored according to atom type) bind to the tetramer. The inhibitor residues and the^ central cavity discussed under "Results and Discussion" are labeled. 		Figure 10.
Fig. 10. Schematic superposition of the ICE and CPP32 tetramers. The two CPP32 dimers are represented by dark and light gray cylinders. The ICE tetramer is not shaded. Thick arrows on the^ ends of the cylinders indicate the active sites. When the superposition is made based on the residues from the first p17/p12 dimers, the^ second dimers differ by a rigid-body rotation of 13°. The rotation axis (dotted arrow) is oriented perpendicular to the 2-fold axis.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (1997, 272, 6539-6547) copyright 1997.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
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
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
18203133 J.F.Stevens, and C.S.Maier (2008).
Acrolein: Sources, metabolism, and biomolecular interactions relevant to human health and disease.
  Mol Nutr Food Res, 52, 7.  
18176785 J.Wang, and Z.Wang (2008).
Negative regulation of caspase 3-cleaved PAK2 activity by protein phosphatase 1.
  Sci China C Life Sci, 51, 1.  
16946729 B.A.Callus, and D.L.Vaux (2007).
Caspase inhibitors: viral, cellular and chemical.
  Cell Death Differ, 14, 73-78.  
17658284 C.Y.Yun, S.Liu, S.F.Lim, T.Wang, B.Y.Chung, J.Jiat Teo, K.H.Chuan, A.S.Soon, K.S.Goh, and Z.Song (2007).
Specific inhibition of caspase-8 and -9 in CHO cells enhances cell viability in batch and fed-batch cultures.
  Metab Eng, 9, 406-418.  
17283333 D.S.Chelur, and M.Chalfie (2007).
Targeted cell killing by reconstituted caspases.
  Proc Natl Acad Sci U S A, 104, 2283-2288.  
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.  
16570872 J.J.Chiang, and K.Truong (2006).
Computational modeling of a new fluorescent biosensor for caspase proteolytic activity improves dynamic range.
  IEEE Trans Nanobioscience, 5, 41-45.  
15880121 H.Viadiu, O.Stemmann, M.W.Kirschner, and T.Walz (2005).
Domain structure of separase and its binding to securin as determined by EM.
  Nat Struct Mol Biol, 12, 552-553.  
16200200 I.N.Lavrik, A.Golks, and P.H.Krammer (2005).
Caspases: pharmacological manipulation of cell death.
  J Clin Invest, 115, 2665-2672.  
15576551 K.Bose, and A.C.Clark (2005).
pH effects on the stability and dimerization of procaspase-3.
  Protein Sci, 14, 24-36.  
16139916 K.Chul Cho, J.Hoon Jeong, H.Jung Chung, C.O.Joe, S.Wan Kim, and T.Gwan Park (2005).
Folate receptor-mediated intracellular delivery of recombinant caspase-3 for inducing apoptosis.
  J Control Release, 108, 121-131.  
15939021 L.W.Yang, and I.Bahar (2005).
Coupling between catalytic site and collective dynamics: a requirement for mechanochemical activity of enzymes.
  Structure, 13, 893-904.  
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.  
15154972 A.Yoshimori, R.Takasawa, and S.Tanuma (2004).
A novel method for evaluation and screening of caspase inhibitory peptides by the amino acid positional fitness score.
  BMC Pharmacol, 4, 7.  
15298760 F.C.Cheng, A.Lin, J.J.Feng, T.Mizoguchi, H.Takekoshi, H.Kubota, Y.Kato, and Y.Naoki (2004).
Effects of chlorella on activities of protein tyrosine phosphatases, matrix metalloproteinases, caspases, cytokine release, B and T cell proliferations, and phorbol ester receptor binding.
  J Med Food, 7, 146-152.  
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.  
15146491 S.Piana, and U.Rothlisberger (2004).
Molecular dynamics simulations of structural changes during procaspase 3 activation.
  Proteins, 55, 932-941.  
15040837 Y.Liu, A.Porta, X.Peng, K.Gengaro, E.B.Cunningham, H.Li, L.A.Dominguez, T.Bellido, and S.Christakos (2004).
Prevention of glucocorticoid-induced apoptosis in osteocytes and osteoblasts by calbindin-D28k.
  J Bone Miner Res, 19, 479-490.  
15090249 C.J.Lai, and J.C.Wu (2003).
A simple kinetic method for rapid mechanistic analysis of reversible enzyme inhibitors.
  Assay Drug Dev Technol, 1, 527-535.  
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
12563278 D.A.Erlanson, J.W.Lam, C.Wiesmann, T.N.Luong, R.L.Simmons, W.L.DeLano, I.C.Choong, M.T.Burdett, W.M.Flanagan, D.Lee, E.M.Gordon, and T.O'Brien (2003).
In situ assembly of enzyme inhibitors using extended tethering.
  Nat Biotechnol, 21, 308-314.
PDB codes: 1nme 1nmq 1nms
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.  
  12969646 V.M.Gun'ko, A.V.Klyueva, Y.N.Levchuk, and R.Leboda (2003).
Photon correlation spectroscopy investigations of proteins.
  Adv Colloid Interface Sci, 105, 201-328.  
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.  
11931755 Y.Shi (2002).
Mechanisms of caspase activation and inhibition during apoptosis.
  Mol Cell, 9, 459-470.  
11294190 H.L.Li, E.Karwatowska-Prokopczuk, M.Mutomba, J.Wu, D.Karanewsky, K.Valentino, R.L.Engler, and R.A.Gottlieb (2001).
Pharmacology of caspase inhibitors in rabbit cardiomyocytes subjected to metabolic inhibition and recovery.
  Antioxid Redox Signal, 3, 113-123.  
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
11750036 K.C.Zimmermann, C.Bonzon, and D.R.Green (2001).
The machinery of programmed cell death.
  Pharmacol Ther, 92, 57-70.  
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
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
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.  
11057900 S.W.Fesik (2000).
Insights into programmed cell death through structural biology.
  Cell, 103, 273-282.  
10896057 S.Y.Park, S.H.Park, I.S.Lee, and J.Y.Kong (2000).
Establishment of a high-throughput screening system for caspase-3 inhibitors.
  Arch Pharm Res, 23, 246-251.  
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
10523290 A.Eichinger, H.G.Beisel, U.Jacob, R.Huber, F.J.Medrano, A.Banbula, J.Potempa, J.Travis, and W.Bode (1999).
Crystal structure of gingipain R: an Arg-specific bacterial cysteine proteinase with a caspase-like fold.
  EMBO J, 18, 5453-5462.
PDB code: 1cvr
10205157 A.J.Fisher, W.Cruz, S.J.Zoog, C.L.Schneider, and P.D.Friesen (1999).
Crystal structure of baculovirus P35: role of a novel reactive site loop in apoptotic caspase inhibition.
  EMBO J, 18, 2031-2039.
PDB code: 1p35
10545333 G.S.Salvesen (1999).
Caspase 8: igniting the death machine.
  Structure, 7, R225-R229.  
10508784 H.Blanchard, L.Kodandapani, P.R.Mittl, S.D.Marco, J.F.Krebs, J.C.Wu, K.J.Tomaselli, and M.G.Grütter (1999).
The three-dimensional structure of caspase-8: an initiator enzyme in apoptosis.
  Structure, 7, 1125-1133.
PDB code: 1qdu
10403638 M.Los, S.Wesselborg, and K.Schulze-Osthoff (1999).
The role of caspases in development, immunity, and apoptotic signal transduction: lessons from knockout mice.
  Immunity, 10, 629-639.  
10204485 P.C.Sandel, and J.G.Monroe (1999).
Negative selection of immature B cells by receptor editing or deletion is determined by site of antigen encounter.
  Immunity, 10, 289-299.  
10446456 R.Mihalik, P.Bauer, I.Peták, P.Krajcsi, A.Marton, E.Kun, and L.Kopper (1999).
Interaction of cytocidal drugs and the inhibition of caspase-3 by 3-nitrosobenzamide.
  Int J Cancer, 82, 875-879.  
10467146 R.Reitzer, K.Gruber, G.Jogl, U.G.Wagner, H.Bothe, W.Buckel, and C.Kratky (1999).
Glutamate mutase from Clostridium cochlearium: the structure of a coenzyme B12-dependent enzyme provides new mechanistic insights.
  Structure, 7, 891-902.
PDB codes: 1cb7 1ccw
9892620 S.A.Susin, H.K.Lorenzo, N.Zamzami, I.Marzo, C.Brenner, N.Larochette, M.C.Prévost, P.M.Alzari, and G.Kroemer (1999).
Mitochondrial release of caspase-2 and -9 during the apoptotic process.
  J Exp Med, 189, 381-394.  
10491581 S.L.Chan, and M.P.Mattson (1999).
Caspase and calpain substrates: roles in synaptic plasticity and cell death.
  J Neurosci Res, 58, 167-190.  
  10551900 S.R.Grobmyer, R.C.Armstrong, S.C.Nicholson, C.Gabay, W.P.Arend, S.H.Potter, M.Melchior, L.C.Fritz, and C.F.Nathan (1999).
Peptidomimetic fluoromethylketone rescues mice from lethal endotoxic shock.
  Mol Med, 5, 585-594.  
10872455 W.C.Earnshaw, L.M.Martins, and S.H.Kaufmann (1999).
Mammalian caspases: structure, activation, substrates, and functions during apoptosis.
  Annu Rev Biochem, 68, 383-424.  
10508785 W.Watt, K.A.Koeplinger, A.M.Mildner, R.L.Heinrikson, A.G.Tomasselli, and K.D.Watenpaugh (1999).
The atomic-resolution structure of human caspase-8, a key activator of apoptosis.
  Structure, 7, 1135-1143.
PDB code: 1qtn
9547337 I.Marzo, C.Brenner, N.Zamzami, S.A.Susin, G.Beutner, D.Brdiczka, R.Rémy, Z.H.Xie, J.C.Reed, and G.Kroemer (1998).
The permeability transition pore complex: a target for apoptosis regulation by caspases and bcl-2-related proteins.
  J Exp Med, 187, 1261-1271.  
9692966 Q.Zhou, J.F.Krebs, S.J.Snipas, A.Price, E.S.Alnemri, K.J.Tomaselli, and G.S.Salvesen (1998).
Interaction of the baculovirus anti-apoptotic protein p35 with caspases. Specificity, kinetics, and characterization of the caspase/p35 complex.
  Biochemistry, 37, 10757-10765.  
9351817 E.Rhéaume, L.Y.Cohen, F.Uhlmann, C.Lazure, A.Alam, J.Hurwitz, R.P.Sékaly, and F.Denis (1997).
The large subunit of replication factor C is a substrate for caspase-3 in vitro and is cleaved by a caspase-3-like protease during Fas-mediated apoptosis.
  EMBO J, 16, 6346-6354.  
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.

 

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