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* Residue conservation analysis
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Gene Ontology (GO) functional annotation
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Cellular component
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cytoplasm
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1 term
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Biological process
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apoptosis
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2 terms
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Biochemical function
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cysteine-type peptidase activity
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2 terms
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DOI no:
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Nat Struct Biol
3:619-625
(1996)
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PubMed id:
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The three-dimensional structure of apopain/CPP32, a key mediator of apoptosis.
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J.Rotonda,
D.W.Nicholson,
K.M.Fazil,
M.Gallant,
Y.Gareau,
M.Labelle,
E.P.Peterson,
D.M.Rasper,
R.Ruel,
J.P.Vaillancourt,
N.A.Thornberry,
J.W.Becker.
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ABSTRACT
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Cysteine proteases related to mammalian interleukin-1 beta converting enzyme
(ICE) and to its Caenorhabditis elegans homologue, CED-3, play a critical role
in the biochemical events that culminate in apoptosis. We have determined the
three-dimensional structure of a complex of the human CED-3 homologue
CPP32/apopain with a potent tetrapeptide-aldehyde inhibitor. The protein
resembles ICE in overall structure, but its S4 subsite is strikingly different
in size and chemical composition. These differences account for the variation in
specificity between the ICE- and CED-3-related proteases and enable the design
of specific inhibitors that can probe the physiological functions of the
proteins and disease states with which they are associated.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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M.Scabini,
F.Stellari,
P.Cappella,
S.Rizzitano,
G.Texido,
and
E.Pesenti
(2011).
In vivo imaging of early stage apoptosis by measuring real-time caspase-3/7 activation.
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| |
Apoptosis, 16,
198-207.
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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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| |
Cell Res, 20,
211-222.
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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.
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X.Geng,
Q.H.Zhou,
E.Kage-Nakadai,
Y.Shi,
N.Yan,
S.Mitani,
and
D.Xue
(2009).
Caenorhabditis elegans caspase homolog CSP-2 inhibits CED-3 autoactivation and apoptosis in germ cells.
|
| |
Cell Death Differ, 16,
1385-1394.
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|
|
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L.Dorstyn,
and
S.Kumar
(2008).
A biochemical analysis of the activation of the Drosophila caspase DRONC.
|
| |
Cell Death Differ, 15,
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|
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S.Roy,
J.R.Sharom,
C.Houde,
T.P.Loisel,
J.P.Vaillancourt,
W.Shao,
M.Saleh,
and
D.W.Nicholson
(2008).
Confinement of caspase-12 proteolytic activity to autoprocessing.
|
| |
Proc Natl Acad Sci U S A, 105,
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X.Geng,
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A.Nakagawa,
S.Yoshina,
S.Mitani,
Y.Shi,
and
D.Xue
(2008).
Inhibition of CED-3 zymogen activation and apoptosis in Caenorhabditis elegans by caspase homolog CSP-3.
|
| |
Nat Struct Mol Biol, 15,
1094-1101.
|
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|
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A.Piekarska,
R.Kubiak,
A.Omulecka,
W.Szymczak,
and
J.Piekarski
(2007).
Expression of tumour necrosis factor-related apoptosis-inducing ligand and caspase-3 in relation to grade of inflammation and stage of fibrosis in chronic hepatitis C.
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| |
Histopathology, 51,
597-604.
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|
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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.
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|
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B.Yoo,
M.S.Raam,
R.M.Rosenblum,
and
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Enzyme-responsive PARACEST MRI contrast agents: a new biomedical imaging approach for studies of the proteasome.
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| |
Contrast Media Mol Imaging, 2,
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D.S.Chelur,
and
M.Chalfie
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Targeted cell killing by reconstituted caspases.
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| |
Proc Natl Acad Sci U S A, 104,
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|
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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.
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A.K.Mitra,
and
D.K.Agrawal
(2006).
In stent restenosis: bane of the stent era.
|
| |
J Clin Pathol, 59,
232-239.
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C.Chakraborty,
G.Saha,
B.Sarkar,
S.Pal,
T.K.Chatterjee,
and
A.K.Sadhu
(2006).
Caspase-3 induced apoptosis in transgenic zebrafish.
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| |
Biotechnol Lett, 28,
189-196.
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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.
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S.R.Dunn,
W.S.Phillips,
J.W.Spatafora,
D.R.Green,
and
V.M.Weis
(2006).
Highly conserved caspase and Bcl-2 homologues from the sea anemone Aiptasia pallida: lower metazoans as models for the study of apoptosis evolution.
|
| |
J Mol Evol, 63,
95.
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D.A.Mitchell,
and
M.A.Marletta
(2005).
Thioredoxin catalyzes the S-nitrosation of the caspase-3 active site cysteine.
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| |
Nat Chem Biol, 1,
154-158.
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H.Liu,
D.W.Chang,
and
X.Yang
(2005).
Interdimer processing and linearity of procaspase-3 activation. A unifying mechanism for the activation of initiator and effector caspases.
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| |
J Biol Chem, 280,
11578-11582.
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I.N.Lavrik,
A.Golks,
and
P.H.Krammer
(2005).
Caspases: pharmacological manipulation of cell death.
|
| |
J Clin Invest, 115,
2665-2672.
|
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|
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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.
|
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|
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M.F.Hsu,
C.J.Kuo,
K.T.Chang,
H.C.Chang,
C.C.Chou,
T.P.Ko,
H.L.Shr,
G.G.Chang,
A.H.Wang,
and
P.H.Liang
(2005).
Mechanism of the maturation process of SARS-CoV 3CL protease.
|
| |
J Biol Chem, 280,
31257-31266.
|
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PDB codes:
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N.Yan,
and
Y.Shi
(2005).
Mechanisms of apoptosis through structural biology.
|
| |
Annu Rev Cell Dev Biol, 21,
35-56.
|
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|
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|
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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.
|
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|
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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.
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A.I.Doseff
(2004).
Apoptosis: the sculptor of development.
|
| |
Stem Cells Dev, 13,
473-483.
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|
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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.
|
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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.
|
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PDB code:
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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.
|
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PDB codes:
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|
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M.Endo,
K.Nakayama,
Y.Kaida,
and
T.Majima
(2004).
Design and synthesis of photochemically controllable caspase-3.
|
| |
Angew Chem Int Ed Engl, 43,
5643-5645.
|
 |
|
|
|
|
 |
N.E.Labrou,
and
D.J.Rigden
(2004).
The structure-function relationship in the clostripain family of peptidases.
|
| |
Eur J Biochem, 271,
983-992.
|
 |
|
|
|
|
 |
S.J.Riedl,
and
Y.Shi
(2004).
Molecular mechanisms of caspase regulation during apoptosis.
|
| |
Nat Rev Mol Cell Biol, 5,
897-907.
|
 |
|
|
|
|
 |
S.Piana,
and
U.Rothlisberger
(2004).
Molecular dynamics simulations of structural changes during procaspase 3 activation.
|
| |
Proteins, 55,
932-941.
|
 |
|
|
|
|
 |
S.Tanuma,
A.Yoshimori,
and
R.Takasawa
(2004).
Genomic drug discovery for apoptosis regulation using a new computer screening amino acid complement wave method.
|
| |
Biol Pharm Bull, 27,
968-973.
|
 |
|
|
|
|
 |
X.Jiang,
and
X.Wang
(2004).
Cytochrome C-mediated apoptosis.
|
| |
Annu Rev Biochem, 73,
87.
|
 |
|
|
|
|
 |
A.K.Liou,
R.S.Clark,
D.C.Henshall,
X.M.Yin,
and
J.Chen
(2003).
To die or not to die for neurons in ischemia, traumatic brain injury and epilepsy: a review on the stress-activated signaling pathways and apoptotic pathways.
|
| |
Prog Neurobiol, 69,
103-142.
|
 |
|
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|
 |
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.
|
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|
PDB code:
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|
 |
C.Houde,
S.Roy,
N.Leung,
D.W.Nicholson,
and
N.Beauchemin
(2003).
The cell adhesion molecule CEACAM1-L is a substrate of caspase-3-mediated cleavage in apoptotic mouse intestinal cells.
|
| |
J Biol Chem, 278,
16929-16935.
|
 |
|
|
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|
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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.
|
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PDB code:
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|
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K.Iwasaki,
K.Mishima,
N.Egashira,
I.H.Al-Khatib,
D.Ishibashi,
K.Irie,
H.Kobayashi,
T.Egawa,
and
M.Fujiwara
(2003).
Effect of nilvadipine on the cerebral ischemia-induced impairment of spatial memory and hippocampal apoptosis in rats.
|
| |
J Pharmacol Sci, 93,
188-196.
|
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|
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M.Radulovic,
C.Hippel,
and
J.Spiess
(2003).
Corticotropin-releasing factor (CRF) rapidly suppresses apoptosis by acting upstream of the activation of caspases.
|
| |
J Neurochem, 84,
1074-1085.
|
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|
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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.
|
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|
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|
 |
M.Sulpizi,
U.Rothlisberger,
and
P.Carloni
(2003).
Molecular dynamics studies of caspase-3.
|
| |
Biophys J, 84,
2207-2215.
|
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|
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|
 |
N.Bizat,
J.M.Hermel,
S.Humbert,
C.Jacquard,
C.Créminon,
C.Escartin,
F.Saudou,
S.Krajewski,
P.Hantraye,
and
E.Brouillet
(2003).
In vivo calpain/caspase cross-talk during 3-nitropropionic acid-induced striatal degeneration: implication of a calpain-mediated cleavage of active caspase-3.
|
| |
J Biol Chem, 278,
43245-43253.
|
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|
 |
W.M.Boedefeld,
K.I.Bland,
and
M.J.Heslin
(2003).
Recent insights into angiogenesis, apoptosis, invasion, and metastasis in colorectal carcinoma.
|
| |
Ann Surg Oncol, 10,
839-851.
|
 |
|
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|
 |
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.
|
 |
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|
 |
E.A.Gaucher,
X.Gu,
M.M.Miyamoto,
and
S.A.Benner
(2002).
Predicting functional divergence in protein evolution by site-specific rate shifts.
|
| |
Trends Biochem Sci, 27,
315-321.
|
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|
 |
H.R.Stennicke,
C.A.Ryan,
and
G.S.Salvesen
(2002).
Reprieval from execution: the molecular basis of caspase inhibition.
|
| |
Trends Biochem Sci, 27,
94.
|
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|
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|
 |
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.
|
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|
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|
 |
L.B.Ruest,
A.Khalyfa,
and
E.Wang
(2002).
Development-dependent disappearance of caspase-3 in skeletal muscle is post-transcriptionally regulated.
|
| |
J Cell Biochem, 86,
21-28.
|
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|
 |
M.Guo,
E.Sato,
A.Jin,
X.Li,
E.Mori,
Y.Xu,
and
T.Mori
(2002).
Human prostate cancer cell death by novel anticancer compounds, apoptosis-inducing nucleosides from CD57+ HLA-DR(bright) natural suppressor cell line.
|
| |
Prostate, 51,
166-174.
|
 |
|
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|
 |
M.S.Shive,
W.G.Brodbeck,
and
J.M.Anderson
(2002).
Activation of caspase 3 during shear stress-induced neutrophil apoptosis on biomaterials.
|
| |
J Biomed Mater Res, 62,
163-168.
|
 |
|
|
|
|
 |
N.Morishima,
K.Nakanishi,
H.Takenouchi,
T.Shibata,
and
Y.Yasuhiko
(2002).
An endoplasmic reticulum stress-specific caspase cascade in apoptosis. Cytochrome c-independent activation of caspase-9 by caspase-12.
|
| |
J Biol Chem, 277,
34287-34294.
|
 |
|
|
|
|
 |
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.
|
 |
|
|
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|
 |
S.K.Vilcheck,
T.J.O'Brien,
D.E.Pritchard,
L.Ha,
S.Ceryak,
J.L.Fornsaglio,
and
S.R.Patierno
(2002).
Fanconi anemia complementation group A cells are hypersensitive to chromium(VI)-induced toxicity.
|
| |
Environ Health Perspect, 110,
773-777.
|
 |
|
|
|
|
 |
Y.Shi
(2002).
Mechanisms of caspase activation and inhibition during apoptosis.
|
| |
Mol Cell, 9,
459-470.
|
 |
|
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|
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B.Yang,
A.M.El Nahas,
G.L.Thomas,
J.L.Haylor,
P.F.Watson,
B.Wagner,
and
T.S.Johnson
(2001).
Caspase-3 and apoptosis in experimental chronic renal scarring.
|
| |
Kidney Int, 60,
1765-1776.
|
 |
|
|
|
|
 |
D.Blum,
S.Torch,
N.Lambeng,
M.Nissou,
A.L.Benabid,
R.Sadoul,
and
J.M.Verna
(2001).
Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson's disease.
|
| |
Prog Neurobiol, 65,
135-172.
|
 |
|
|
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|
 |
J.C.Reed
(2001).
Apoptosis-regulating proteins as targets for drug discovery.
|
| |
Trends Mol Med, 7,
314-319.
|
 |
|
|
|
|
 |
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:
|
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|
 |
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:
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|
 |
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:
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|
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K.C.Zimmermann,
C.Bonzon,
and
D.R.Green
(2001).
The machinery of programmed cell death.
|
| |
Pharmacol Ther, 92,
57-70.
|
 |
|
|
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|
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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:
|
 |
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|
 |
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:
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
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only a partial list as not all journals are covered by
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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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