PDBsum entry 1i3o

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protein metals Protein-protein interface(s) links
Apoptosis PDB id
Protein chains
143 a.a. *
101 a.a. *
111 a.a. *
93 a.a. *
_ZN ×2
Waters ×13
* Residue conservation analysis
PDB id:
Name: Apoptosis
Title: Crystal structure of the complex of xiap-bir2 and caspase 3
Structure: Caspase 3. Chain: a, c. Fragment: apopain p17 subunit. Engineered: yes. Mutation: yes. Caspase 3. Chain: b, d. Fragment: apopain p12 subunit. Engineered: yes.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: i39005. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Gene: u32974.
Biol. unit: Hexamer (from PQS)
2.70Å     R-factor:   0.248     R-free:   0.278
Authors: S.J.Riedl,M.Renatus,R.Schwarzenbacher,Q.Zhou,C.Sun, S.W.Fesik,R.C.Liddington,G.S.Salvesen
Key ref:
S.J.Riedl et al. (2001). Structural basis for the inhibition of caspase-3 by XIAP. Cell, 104, 791-800. PubMed id: 11257232 DOI: 10.1016/S0092-8674(01)00274-4
15-Feb-01     Release date:   21-Mar-01    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P42574  (CASP3_HUMAN) -  Caspase-3
277 a.a.
143 a.a.*
Protein chains
Pfam   ArchSchema ?
P42574  (CASP3_HUMAN) -  Caspase-3
277 a.a.
101 a.a.
Protein chain
Pfam   ArchSchema ?
P98170  (XIAP_HUMAN) -  E3 ubiquitin-protein ligase XIAP
497 a.a.
111 a.a.*
Protein chain
Pfam   ArchSchema ?
P98170  (XIAP_HUMAN) -  E3 ubiquitin-protein ligase XIAP
497 a.a.
93 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 5 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: Chains A, B, C, D: E.C.  - Caspase-3.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytoplasm   1 term 
  Biological process     apoptotic process   2 terms 
  Biochemical function     cysteine-type peptidase activity     2 terms  


DOI no: 10.1016/S0092-8674(01)00274-4 Cell 104:791-800 (2001)
PubMed id: 11257232  
Structural basis for the inhibition of caspase-3 by XIAP.
S.J.Riedl, M.Renatus, R.Schwarzenbacher, Q.Zhou, C.Sun, S.W.Fesik, R.C.Liddington, G.S.Salvesen.
The molecular mechanism(s) that regulate apoptosis by caspase inhibition remain poorly understood. The main endogenous inhibitors are members of the IAP family and are exemplified by XIAP, which regulates the initiator caspase-9, and the executioner caspases-3 and -7. We report the crystal structure of the second BIR domain of XIAP (BIR2) in complex with caspase-3, at a resolution of 2.7 A, revealing the structural basis for inhibition. The inhibitor makes limited contacts through its BIR domain to the surface of the enzyme, and most contacts to caspase-3 originate from the N-terminal extension. This lies across the substrate binding cleft, but in reverse orientation compared to substrate binding. The mechanism of inhibition is due to a steric blockade prohibitive of substrate binding, and is distinct from the mechanism utilized by synthetic substrate analog inhibitors.
  Selected figure(s)  
Figure 1.
Figure 1. Standard View of Caspase-3 with BIR2 Domains BoundThe asymmetric unit is composed of two caspase-3 catalytic domains (blue and purple), each one binding a BIR2 molecule (green). The large and small subunits of each catalytic domain are shaded differently. Each BIR2 molecule constitutes a globular domain and an N-terminal extension occupying the catalytic edge of each caspase. The pink sphere at the core of each BIR domain is the zinc atom
Figure 4.
Figure 4. Mechanism of Inhibition(A) The BIR2 hook region (green) is superimposed on the structure of the substrate analog DEVD-aldehyde (in brown) bound to caspase-3, with its catalytic residues H237 and C285 shown in gray (1PAU; Rotonda et al., 1996). The distance from Sγ of the catalytic Cys to the carbonyl carbon of the substrate analog is 1.8 Å, but the closest approach of a BIR2 carbonyl is 5.8 Å, well out of the reach of atomic interactions.(B) Focus on the substrate binding region of caspase-3, and comparison of DEVD-aldehyde and BIR2 binding interactions. The trace of BIR2 (green) is superimposed on the caspase-3 structure with DEVD-aldehyde (brown) bound. Two caspase-3 side chains (Y338 and F381h) that occupy different rotamers in the two complexes are highlighted. In blue is their position in the BIR2 structure, and in gray is their position in the DEVD-aldehyde structure. To the left of the panel the side chain of D148 of BIR2 and the topologically equivalent P4 Asp residue of DEVD-aldehyde are shown.(C) The interaction between BIR and caspase-3 or -7 was observed by nondenaturing and SDS-PAGE. A 1.2-fold molar excess of BIR2 was incubated with wild-type (wt) caspase-3 or caspase-7, or C285A caspase-3 (mut), and complex formation visualized as a gel shift in nondenaturing PAGE. Binding of BIR2 could be prevented by pretreating caspase-3 with Z-VAD-fmk. The complex was dissociated in SDS-PAGE (top panel), and no cleavage of BIR2 was observed
  The above figures are reprinted by permission from Cell Press: Cell (2001, 104, 791-800) copyright 2001.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
22293567 S.Fulda, and D.Vucic (2012).
Targeting IAP proteins for therapeutic intervention in cancer.
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Naringenin up-regulates the expression of death receptor 5 and enhances TRAIL-induced apoptosis in human lung cancer A549 cells.
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21349322 L.Yang, W.Li, Z.Tian, J.Zhao, and C.Wang (2011).
Mononaphthalimide spermidine conjugate induces cell proliferation inhibition and apoptosis in HeLa cells.
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21340509 M.Orzáez, A.Gortat, M.Sancho, R.J.Carbajo, A.Pineda-Lucena, Y.Palacios-Rodríguez, and E.Pérez-Payá (2011).
Characterization of dequalinium as a XIAP antagonist that targets the BIR2 domain.
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20632385 A.R.Hussain, S.Uddin, M.Ahmed, R.Bu, S.O.Ahmed, J.Abubaker, M.Sultana, D.Ajarim, F.Al-Dayel, P.P.Bavi, and K.S.Al-Kuraya (2010).
Prognostic significance of XIAP expression in DLBCL and effect of its inhibition on AKT signalling.
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20704571 D.C.Altieri (2010).
Survivin and IAP proteins in cell-death mechanisms.
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20954235 F.Cossu, F.Malvezzi, G.Canevari, E.Mastrangelo, D.Lecis, D.Delia, P.Seneci, C.Scolastico, M.Bolognesi, and M.Milani (2010).
Recognition of Smac-mimetic compounds by the BIR domain of cIAP1.
  Protein Sci, 19, 2418-2429.
PDB codes: 3mup 3oz1
20651737 M.Gyrd-Hansen, and P.Meier (2010).
IAPs: from caspase inhibitors to modulators of NF-kappaB, inflammation and cancer.
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19373243 P.D.Mace, S.Shirley, and C.L.Day (2010).
Assembling the building blocks: structure and function of inhibitor of apoptosis proteins.
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20682068 P.Kumar, A.Yadav, S.N.Patel, M.Islam, Q.Pan, S.D.Merajver, and T.N.Teknos (2010).
Tetrathiomolybdate inhibits head and neck cancer metastasis by decreasing tumor cell motility, invasiveness and by promoting tumor cell anoikis.
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20148665 R.S.Whelan, V.Kaplinskiy, and R.N.Kitsis (2010).
Cell death in the pathogenesis of heart disease: mechanisms and significance.
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20606168 S.M.Leong, B.X.Tan, B.Bte Ahmad, T.Yan, L.Y.Chee, S.T.Ang, K.G.Tay, L.P.Koh, A.E.Yeoh, E.S.Koay, Y.K.Mok, and T.M.Lim (2010).
Mutant nucleophosmin deregulates cell death and myeloid differentiation through excessive caspase-6 and -8 inhibition.
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20119620 T.Zhang, M.Wu, Q.Chen, and Z.Sun (2010).
Investigation into the regulation mechanisms of TRAIL apoptosis pathway by mathematical modeling.
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20510932 Z.Li, J.Jo, J.M.Jia, S.C.Lo, D.J.Whitcomb, S.Jiao, K.Cho, and M.Sheng (2010).
Caspase-3 activation via mitochondria is required for long-term depression and AMPA receptor internalization.
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19283487 B.Fang, G.Fu, J.Agniswamy, R.W.Harrison, and I.T.Weber (2009).
Caspase-3 binds diverse P4 residues in peptides as revealed by crystallography and structural modeling.
  Apoptosis, 14, 741-752.
PDB codes: 3gjq 3gjr 3gjs 3gjt
19660030 C.D.Moore, H.Wu, B.Bolaños, S.Bergqvist, A.Brooun, T.Pauly, and D.Nowlin (2009).
Structural and biophysical characterization of XIAP BIR3 G306E mutant: insights in protein dynamics and application for fragment-based drug design.
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19500649 H.M.Bramlett, O.Furones-Alonso, G.Lotocki, A.Rodriguez-Paez, J.Sanchez-Molano, and R.W.Keane (2009).
Sex differences in XIAP cleavage after traumatic brain injury in the rat.
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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
19143833 J.R.Pungercar, D.Caglic, M.Sajid, M.Dolinar, O.Vasiljeva, U.Pozgan, D.Turk, M.Bogyo, V.Turk, and B.Turk (2009).
Autocatalytic processing of procathepsin B is triggered by proenzyme activity.
  FEBS J, 276, 660-668.  
19411066 L.Gu, N.Zhu, H.Zhang, D.L.Durden, Y.Feng, and M.Zhou (2009).
Regulation of XIAP translation and induction by MDM2 following irradiation.
  Cancer Cell, 15, 363-375.  
19338579 L.Ottonello, M.Bertolotto, F.Montecucco, G.Bianchi, and F.Dallegri (2009).
Delayed apoptosis of human monocytes exposed to immune complexes is reversed by oxaprozin: role of the Akt/IkappaB kinase/nuclear factor kappaB pathway.
  Br J Pharmacol, 157, 294-306.  
19217783 M.Broemer, and P.Meier (2009).
Ubiquitin-mediated regulation of apoptosis.
  Trends Cell Biol, 19, 130-140.  
  19923725 M.D.Herman, M.Moche, S.Flodin, M.Welin, L.Trésaugues, I.Johansson, M.Nilsson, P.Nordlund, and T.Nyman (2009).
Structures of BIR domains from human NAIP and cIAP2.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 65, 1091-1096.
PDB codes: 2uvl 2vm5
19415464 M.Danquah, F.Li, C.B.Duke, D.D.Miller, and R.I.Mahato (2009).
Micellar delivery of bicalutamide and embelin for treating prostate cancer.
  Pharm Res, 26, 2081-2092.  
19758996 M.E.Shawgo, S.N.Shelton, and J.D.Robertson (2009).
Caspase-9 activation by the apoptosome is not required for fas-mediated apoptosis in type II Jurkat cells.
  J Biol Chem, 284, 33447-33455.  
19877056 M.Ferretti, M.Gattorno, A.Chiocchetti, R.Mesturini, E.Orilieri, T.Bensi, M.P.Sormani, G.Cappellano, E.Cerutti, S.Nicola, A.Biava, C.Bardelli, S.Federici, I.Ceccherini, M.Baldi, C.Santoro, I.Dianzani, A.Martini, and U.Dianzani (2009).
The 423Q polymorphism of the X-linked inhibitor of apoptosis gene influences monocyte function and is associated with periodic fever.
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19148180 P.Clarke, and K.L.Tyler (2009).
Apoptosis in animal models of virus-induced disease.
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19039324 S.Fulda (2009).
Inhibitor of apoptosis proteins in hematological malignancies.
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19298593 S.Fulda (2009).
Therapeutic opportunities for counteracting apoptosis resistance in childhood leukaemia.
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19147789 S.H.Cho, S.Goenka, T.Henttinen, P.Gudapati, A.Reinikainen, C.M.Eischen, R.Lahesmaa, and M.Boothby (2009).
PARP-14, a member of the B aggressive lymphoma family, transduces survival signals in primary B cells.
  Blood, 113, 2416-2425.  
19258326 Y.E.Choi, M.Butterworth, S.Malladi, C.S.Duckett, G.M.Cohen, and S.B.Bratton (2009).
The E3 Ubiquitin Ligase cIAP1 Binds and Ubiquitinates Caspase-3 and -7 via Unique Mechanisms at Distinct Steps in Their Processing.
  J Biol Chem, 284, 12772-12782.  
18708583 A.J.Schile, M.García-Fernández, and H.Steller (2008).
Regulation of apoptosis by XIAP ubiquitin-ligase activity.
  Genes Dev, 22, 2256-2266.  
19088744 A.V.Sintsov, E.I.Kovalenko, and M.A.Khanin (2008).
[Apoptosis induced by granzyme B.]
  Bioorg Khim, 34, 725-733.  
18239672 B.P.Eckelman, M.Drag, S.J.Snipas, and G.S.Salvesen (2008).
The mechanism of peptide-binding specificity of IAP BIR domains.
  Cell Death Differ, 15, 920-928.  
18438971 C.Obiol-Pardo, J.M.Granadino-Roldán, and J.Rubio-Martinez (2008).
Protein-protein recognition as a first step towards the inhibition of XIAP and Survivin anti-apoptotic proteins.
  J Mol Recognit, 21, 190-204.  
18553460 D.O.Croci, I.S.Cogno, N.B.Vittar, E.Salvatierra, F.Trajtenberg, O.L.Podhajcer, E.Osinaga, G.A.Rabinovich, and V.A.Rivarola (2008).
Silencing survivin gene expression promotes apoptosis of human breast cancer cells through a caspase-independent pathway.
  J Cell Biochem, 105, 381-390.  
18668521 E.W.Bradley, M.M.Ruan, and M.J.Oursler (2008).
PAK1 is a novel MEK-independent raf target controlling expression of the IAP survivin in M-CSF-mediated osteoclast survival.
  J Cell Physiol, 217, 752-758.  
18937395 H.Sun, Z.Nikolovska-Coleska, C.Y.Yang, D.Qian, J.Lu, S.Qiu, L.Bai, Y.Peng, Q.Cai, and S.Wang (2008).
Design of small-molecule peptidic and nonpeptidic Smac mimetics.
  Acc Chem Res, 41, 1264-1277.  
17967870 J.C.Wilkinson, A.S.Wilkinson, S.Galbán, R.A.Csomos, and C.S.Duckett (2008).
Apoptosis-inducing factor is a target for ubiquitination through interaction with XIAP.
  Mol Cell Biol, 28, 237-247.  
19010913 J.Lu, L.Bai, H.Sun, Z.Nikolovska-Coleska, D.McEachern, S.Qiu, R.S.Miller, H.Yi, S.Shangary, Y.Sun, J.L.Meagher, J.A.Stuckey, and S.Wang (2008).
SM-164: a novel, bivalent Smac mimetic that induces apoptosis and tumor regression by concurrent removal of the blockade of cIAP-1/2 and XIAP.
  Cancer Res, 68, 9384-9393.  
18854135 M.X.O'Riordan, L.D.Bauler, F.L.Scott, and C.S.Duckett (2008).
Inhibitor of apoptosis proteins in eukaryotic evolution and development: a model of thematic conservation.
  Dev Cell, 15, 497-508.  
18338251 P.Maycotte, S.Blancas, and J.Morán (2008).
Role of inhibitor of apoptosis proteins and Smac/DIABLO in staurosporine-induced cerebellar granule neurons death.
  Neurochem Res, 33, 1534-1540.  
18620520 S.M.Langemeijer, Graaf, and J.H.Jansen (2008).
IAPs as therapeutic targets in haematological malignancies.
  Expert Opin Ther Targets, 12, 981-993.  
18818484 Y.Cheng, A.Maeda, Y.Goto, F.Matsuda, T.Miyano, N.Inoue, K.Sakamaki, and N.Manabe (2008).
Changes in Expression and Localization of X-linked Inhibitor of Apoptosis Protein (XIAP) in Follicular Granulosa Cells During Atresia in Porcine Ovaries.
  J Reprod Dev, 54, 454-459.  
19016849 Y.Sasaki, M.Minamizawa, A.Ambo, S.Sugawara, Y.Ogawa, and K.Nitta (2008).
Cell-penetrating peptide-conjugated XIAP-inhibitory cyclic hexapeptides enter into Jurkat cells and inhibit cell proliferation.
  FEBS J, 275, 6011-6021.  
18717598 Z.Nikolovska-Coleska, J.L.Meagher, S.Jiang, C.Y.Yang, S.Qiu, P.P.Roller, J.A.Stuckey, and S.Wang (2008).
Interaction of a cyclic, bivalent smac mimetic with the x-linked inhibitor of apoptosis protein.
  Biochemistry, 47, 9811-9824.
PDB code: 2vsl
  19079792 Z.Wang, and L.M.Pelus (2008).
Disruption of Survivin in K562 cells elevates telomerase activity and protects cells against apoptosis induced by the Bcr-abl kinase inhibitor STI571.
  Cancer Ther, 6, 603-610.  
16911566 A.Abu-Zant, S.Jones, R.Asare, J.Suttles, C.Price, J.Graham, and Y.A.Kwaik (2007).
Anti-apoptotic signalling by the Dot/Icm secretion system of L. pneumophila.
  Cell Microbiol, 9, 246-264.  
17094177 A.Kurakin, and D.E.Bredesen (2007).
An unconventional IAP-binding motif revealed by target-assisted iterative screening (TAIS) of the BIR3-cIAP1 domain.
  J Mol Recognit, 20, 39-50.  
17382285 A.R.Mufti, E.Burstein, and C.S.Duckett (2007).
XIAP: cell death regulation meets copper homeostasis.
  Arch Biochem Biophys, 463, 168-174.  
16946729 B.A.Callus, and D.L.Vaux (2007).
Caspase inhibitors: viral, cellular and chemical.
  Cell Death Differ, 14, 73-78.  
17294084 B.Nachmias, I.Lazar, M.Elmalech, I.Abed-El-Rahaman, Y.Asshab, O.Mandelboim, R.Perlman, and D.Ben-Yehuda (2007).
Subcellular localization determines the delicate balance between the anti- and pro-apoptotic activity of Livin.
  Apoptosis, 12, 1129-1142.  
18034418 B.Nachmias, S.Mizrahi, M.Elmalech, I.Lazar, Y.Ashhab, R.Gazit, G.Markel, D.Ben-Yehuda, and O.Mandelboim (2007).
Manipulation of NK cytotoxicity by the IAP family member Livin.
  Eur J Immunol, 37, 3467-3476.  
17999504 H.Sun, Z.Nikolovska-Coleska, J.Lu, J.L.Meagher, C.Y.Yang, S.Qiu, Y.Tomita, Y.Ueda, S.Jiang, K.Krajewski, P.P.Roller, J.A.Stuckey, and S.Wang (2007).
Design, synthesis, and characterization of a potent, nonpeptide, cell-permeable, bivalent Smac mimetic that concurrently targets both the BIR2 and BIR3 domains in XIAP.
  J Am Chem Soc, 129, 15279-15294.  
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
17450518 J.Y.Liou, N.Matijevic-Aleksic, S.Lee, and K.K.Wu (2007).
Prostacyclin inhibits endothelial cell XIAP ubiquitination and degradation.
  J Cell Physiol, 212, 840-848.  
  17641843 L.Wang, Y.Bi, F.Zeng, L.Zheng, and Q.Tong (2007).
Expression of X-linked inhibitor of apoptosis protein and its effect on chemotherapeutic sensitivity of bladder carcinoma.
  J Huazhong Univ Sci Technolog Med Sci, 27, 285-287.  
17505517 M.H.Malcles, H.W.Wang, A.Koumi, Y.H.Tsai, M.Yu, A.Godfrey, and C.Boshoff (2007).
Characterisation of the anti-apoptotic function of survivin-DeltaEx3 during TNFalpha-mediated cell death.
  Br J Cancer, 96, 1659-1666.  
17560374 M.Lu, S.C.Lin, Y.Huang, Y.J.Kang, R.Rich, Y.C.Lo, D.Myszka, J.Han, and H.Wu (2007).
XIAP induces NF-kappaB activation via the BIR1/TAB1 interaction and BIR1 dimerization.
  Mol Cell, 26, 689-702.
PDB codes: 2poi 2pom 2pop
18166655 P.S.Ribeiro, E.Kuranaga, T.Tenev, F.Leulier, M.Miura, and P.Meier (2007).
DIAP2 functions as a mechanism-based regulator of drICE that contributes to the caspase activity threshold in living cells.
  J Cell Biol, 179, 1467-1480.  
17698078 S.C.Lin, Y.Huang, Y.C.Lo, M.Lu, and H.Wu (2007).
Crystal structure of the BIR1 domain of XIAP in two crystal forms.
  J Mol Biol, 372, 847-854.
PDB code: 2qra
17892425 S.Fulda (2007).
Inhibitor of apoptosis proteins as targets for anticancer therapy.
  Expert Rev Anticancer Ther, 7, 1255-1264.  
17896835 U.Fischer, K.Janssen, and K.Schulze-Osthoff (2007).
Cutting-edge apoptosis-based therapeutics: a panacea for cancer?
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17724022 Z.Gao, Y.Tian, J.Wang, Q.Yin, H.Wu, Y.M.Li, and X.Jiang (2007).
A dimeric Smac/diablo peptide directly relieves caspase-3 inhibition by XIAP. Dynamic and cooperative regulation of XIAP by Smac/Diablo.
  J Biol Chem, 282, 30718-30727.  
16322751 A.D.Schimmer, S.Dalili, R.A.Batey, and S.J.Riedl (2006).
Targeting XIAP for the treatment of malignancy.
  Cell Death Differ, 13, 179-188.  
17040621 A.D.Schimmer (2006).
Induction of apoptosis in lymphoid and myeloid leukemia.
  Curr Oncol Rep, 8, 430-436.  
16326109 A.J.Watson (2006).
An overview of apoptosis and the prevention of colorectal cancer.
  Crit Rev Oncol Hematol, 57, 107-121.  
16543147 A.R.Mufti, E.Burstein, R.A.Csomos, P.C.Graf, J.C.Wilkinson, R.D.Dick, M.Challa, J.K.Son, S.B.Bratton, G.L.Su, G.J.Brewer, U.Jakob, and C.S.Duckett (2006).
XIAP Is a copper binding protein deregulated in Wilson's disease and other copper toxicosis disorders.
  Mol Cell, 21, 775-785.  
17016456 B.P.Eckelman, G.S.Salvesen, and F.L.Scott (2006).
Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family.
  EMBO Rep, 7, 988-994.  
16339151 B.P.Eckelman, and G.S.Salvesen (2006).
The human anti-apoptotic proteins cIAP1 and cIAP2 bind but do not inhibit caspases.
  J Biol Chem, 281, 3254-3260.  
17032165 D.L.Hodge, J.J.Subleski, D.A.Reynolds, M.D.Buschman, W.B.Schill, M.W.Burkett, A.M.Malyguine, and H.A.Young (2006).
The proinflammatory cytokine interleukin-18 alters multiple signaling pathways to inhibit natural killer cell death.
  J Interferon Cytokine Res, 26, 706-718.  
16892093 L.Galluzzi, N.Larochette, N.Zamzami, and G.Kroemer (2006).
Mitochondria as therapeutic targets for cancer chemotherapy.
  Oncogene, 25, 4812-4830.  
16608851 M.A.Salako, M.J.Carter, and G.E.Kass (2006).
Coxsackievirus protein 2BC blocks host cell apoptosis by inhibiting caspase-3.
  J Biol Chem, 281, 16296-16304.  
19617919 S.K.Sharma, C.Straub, and L.Zawel (2006).
Development of Peptidomimetics Targeting IAPs.
  Int J Pept Res Ther, 12, 21-32.  
16978046 S.Legewie, N.Blüthgen, and H.Herzel (2006).
Mathematical modeling identifies inhibitors of apoptosis as mediators of positive feedback and bistability.
  PLoS Comput Biol, 2, e120.  
16847054 X.H.Peng, P.Karna, Z.Cao, B.H.Jiang, M.Zhou, and L.Yang (2006).
Cross-talk between epidermal growth factor receptor and hypoxia-inducible factor-1alpha signal pathways increases resistance to apoptosis by up-regulating survivin gene expression.
  J Biol Chem, 281, 25903-25914.  
16313474 B.Fadeel, and S.Orrenius (2005).
Apoptosis: a basic biological phenomenon with wide-ranging implications in human disease.
  J Intern Med, 258, 479-517.  
15687241 B.Z.Carter, M.Gronda, Z.Wang, K.Welsh, C.Pinilla, M.Andreeff, W.D.Schober, A.Nefzi, G.R.Pond, I.A.Mawji, R.A.Houghten, J.Ostresh, J.Brandwein, M.D.Minden, A.C.Schuh, R.A.Wells, H.Messner, K.Chun, J.C.Reed, and A.D.Schimmer (2005).
Small-molecule XIAP inhibitors derepress downstream effector caspases and induce apoptosis of acute myeloid leukemia cells.
  Blood, 105, 4043-4050.  
15650747 F.L.Scott, J.B.Denault, S.J.Riedl, H.Shin, M.Renatus, and G.S.Salvesen (2005).
XIAP inhibits caspase-3 and -7 using two binding sites: evolutionarily conserved mechanism of IAPs.
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16200200 I.N.Lavrik, A.Golks, and P.H.Krammer (2005).
Caspases: pharmacological manipulation of cell death.
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15909109 K.Higashi, R.Takasawa, A.Yoshimori, T.Goh, S.Tanuma, and K.Kuchitsu (2005).
Identification of a novel gene family, paralogs of inhibitor of apoptosis proteins present in plants, fungi, and animals.
  Apoptosis, 10, 471-480.  
16044155 K.M.Bockbrader, M.Tan, and Y.Sun (2005).
A small molecule Smac-mimic compound induces apoptosis and sensitizes TRAIL- and etoposide-induced apoptosis in breast cancer cells.
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16212486 N.Yan, and Y.Shi (2005).
Mechanisms of apoptosis through structural biology.
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16246265 N.Zhang, H.Hartig, I.Dzhagalov, D.Draper, and Y.W.He (2005).
The role of apoptosis in the development and function of T lymphocytes.
  Cell Res, 15, 749-769.  
15797833 P.Cashio, T.V.Lee, and A.Bergmann (2005).
Genetic control of programmed cell death in Drosophila melanogaster.
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  15791949 P.Clarke, S.M.Richardson-Burns, R.L.DeBiasi, and K.L.Tyler (2005).
Mechanisms of apoptosis during reovirus infection.
  Curr Top Microbiol Immunol, 289, 1.  
15731262 Q.Li, P.Liston, N.Schokman, J.M.Ho, and R.W.Moyer (2005).
Amsacta moorei Entomopoxvirus inhibitor of apoptosis suppresses cell death by binding Grim and Hid.
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15765138 R.S.Foo, K.Mani, and R.N.Kitsis (2005).
Death begets failure in the heart.
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16239906 S.W.Fesik (2005).
Promoting apoptosis as a strategy for cancer drug discovery.
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15580265 T.Tenev, A.Zachariou, R.Wilson, M.Ditzel, and P.Meier (2005).
IAPs are functionally non-equivalent and regulate effector caspases through distinct mechanisms.
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15665817 U.Fischer, and K.Schulze-Osthoff (2005).
Apoptosis-based therapies and drug targets.
  Cell Death Differ, 12, 942-961.  
14749124 A.D.Schimmer, K.Welsh, C.Pinilla, Z.Wang, M.Krajewska, M.J.Bonneau, I.M.Pedersen, S.Kitada, F.L.Scott, B.Bailly-Maitre, G.Glinsky, D.Scudiero, E.Sausville, G.Salvesen, A.Nefzi, J.M.Ostresh, R.A.Houghten, and J.C.Reed (2004).
Small-molecule antagonists of apoptosis suppressor XIAP exhibit broad antitumor activity.
  Cancer Cell, 5, 25-35.  
14993223 D.Twiddy, D.G.Brown, C.Adrain, R.Jukes, S.J.Martin, G.M.Cohen, M.MacFarlane, and K.Cain (2004).
Pro-apoptotic proteins released from the mitochondria regulate the protein composition and caspase-processing activity of the native Apaf-1/caspase-9 apoptosome complex.
  J Biol Chem, 279, 19665-19682.  
14685266 E.Burstein, L.Ganesh, R.D.Dick, B.van De Sluis, J.C.Wilkinson, L.W.Klomp, C.Wijmenga, G.J.Brewer, G.J.Nabel, and C.S.Duckett (2004).
A novel role for XIAP in copper homeostasis through regulation of MURR1.
  EMBO J, 23, 244-254.  
15372573 G.F.Prunell, and C.M.Troy (2004).
Balancing neuronal death.
  J Neurosci Res, 78, 1-6.  
15371430 J.C.Wilkinson, B.W.Richter, A.S.Wilkinson, E.Burstein, J.M.Rumble, B.Balliu, and C.S.Duckett (2004).
VIAF, a conserved inhibitor of apoptosis (IAP)-interacting factor that modulates caspase activation.
  J Biol Chem, 279, 51091-51099.  
15282301 J.C.Wilkinson, E.Cepero, L.H.Boise, and C.S.Duckett (2004).
Upstream regulatory role for XIAP in receptor-mediated apoptosis.
  Mol Cell Biol, 24, 7003-7014.  
14701799 J.Lewis, E.Burstein, S.B.Reffey, S.B.Bratton, A.B.Roberts, and C.S.Duckett (2004).
Uncoupling of the signaling and caspase-inhibitory properties of X-linked inhibitor of apoptosis.
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15161430 M.Holcík (2004).
Targeting endogenous inhibitors of apoptosis for treatment of cancer, stroke and multiple sclerosis.
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14678329 M.Molmeret, S.D.Zink, L.Han, A.Abu-Zant, R.Asari, D.M.Bitar, and Y.Abu Kwaik (2004).
Activation of caspase-3 by the Dot/Icm virulence system is essential for arrested biogenesis of the Legionella-containing phagosome.
  Cell Microbiol, 6, 33-48.  
15107838 N.Yan, J.W.Wu, J.Chai, W.Li, and Y.Shi (2004).
Molecular mechanisms of DrICE inhibition by DIAP1 and removal of inhibition by Reaper, Hid and Grim.
  Nat Struct Mol Biol, 11, 420-428.
PDB codes: 1sdz 1se0
15305862 P.Garnier, A.Prigent-Tessier, M.Van Hoecke, N.Bertrand, C.Demougeot, O.Sordet, R.A.Swanson, C.Marie, and A.Beley (2004).
Hypoxia induces caspase-9 and caspase-3 activation without neuronal death in gerbil brains.
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15340445 S.J.Martin (2004).
An Apollon vista of death and destruction.
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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.
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15189137 X.Jiang, and X.Wang (2004).
Cytochrome C-mediated apoptosis.
  Annu Rev Biochem, 73, 87.  
15383280 Y.J.Nam, K.Mani, A.W.Ashton, C.F.Peng, B.Krishnamurthy, Y.Hayakawa, P.Lee, S.J.Korsmeyer, and R.N.Kitsis (2004).
Inhibition of both the extrinsic and intrinsic death pathways through nonhomotypic death-fold interactions.
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15273300 Y.Shi (2004).
Caspase activation, inhibition, and reactivation: a mechanistic view.
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15117963 Y.Zong, T.W.Bice, H.Ton-That, O.Schneewind, and S.V.Narayana (2004).
Crystal structures of Staphylococcus aureus sortase A and its substrate complex.
  J Biol Chem, 279, 31383-31389.
PDB codes: 1t2o 1t2p 1t2w
14699067 Z.Song, S.Liu, H.He, N.Hoti, Y.Wang, S.Feng, and M.Wu (2004).
A single amino acid change (Asp 53 --> Ala53) converts Survivin from anti-apoptotic to pro-apoptotic.
  Mol Biol Cell, 15, 1287-1296.  
15337764 Z.Wang, M.Cuddy, T.Samuel, K.Welsh, A.Schimmer, F.Hanaii, R.Houghten, C.Pinilla, and J.C.Reed (2004).
Cellular, biochemical, and genetic analysis of mechanism of small molecule IAP inhibitors.
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14644196 A.Bergmann, A.Y.Yang, and M.Srivastava (2003).
Regulators of IAP function: coming to grips with the grim reaper.
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12576135 A.Clerk, S.M.Cole, T.E.Cullingford, J.G.Harrison, M.Jormakka, and D.M.Valks (2003).
Regulation of cardiac myocyte cell death.
  Pharmacol Ther, 97, 223-261.  
12887052 C.A.Ryan, and G.S.Salvesen (2003).
Caspases and neuronal development.
  Biol Chem, 384, 855-861.  
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
12767258 E.Ferraro, M.Corvaro, and F.Cecconi (2003).
Physiological and pathological roles of Apaf1 and the apoptosome.
  J Cell Mol Med, 7, 21-34.  
12620238 E.N.Shiozaki, J.Chai, D.J.Rigotti, S.J.Riedl, P.Li, S.M.Srinivasula, E.S.Alnemri, R.Fairman, and Y.Shi (2003).
Mechanism of XIAP-mediated inhibition of caspase-9.
  Mol Cell, 11, 519-527.
PDB code: 1nw9
12773388 H.Marusawa, S.Matsuzawa, K.Welsh, H.Zou, R.Armstrong, I.Tamm, and J.C.Reed (2003).
HBXIP functions as a cofactor of survivin in apoptosis suppression.
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12648453 I.S.Goping, M.Barry, P.Liston, T.Sawchuk, G.Constantinescu, K.M.Michalak, I.Shostak, D.L.Roberts, A.M.Hunter, R.Korneluk, and R.C.Bleackley (2003).
Granzyme B-induced apoptosis requires both direct caspase activation and relief of caspase inhibition.
  Immunity, 18, 355-365.  
12538646 I.Tamm, M.Trepel, M.Cardó-Vila, Y.Sun, K.Welsh, E.Cabezas, A.Swatterthwait, W.Arap, J.C.Reed, and R.Pasqualini (2003).
Peptides targeting caspase inhibitors.
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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.  
12446669 M.R.Olson, C.L.Holley, S.J.Yoo, J.R.Huh, B.A.Hay, and S.Kornbluth (2003).
Reaper is regulated by IAP-mediated ubiquitination.
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12890028 M.Rzychon, A.Sabat, K.Kosowska, J.Potempa, and A.Dubin (2003).
Staphostatins: an expanding new group of proteinase inhibitors with a unique specificity for the regulation of staphopains, Staphylococcus spp. cysteine proteinases.
  Mol Microbiol, 49, 1051-1066.  
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.
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12668429 M.Sulpizi, U.Rothlisberger, and P.Carloni (2003).
Molecular dynamics studies of caspase-3.
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12766759 N.Inohara, and G.Nuñez (2003).
NODs: intracellular proteins involved in inflammation and apoptosis.
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12767037 P.Hersey, and X.D.Zhang (2003).
Overcoming resistance of cancer cells to apoptosis.
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12738057 S.K.Ray, E.L.Hogan, and N.L.Banik (2003).
Calpain in the pathophysiology of spinal cord injury: neuroprotection with calpain inhibitors.
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Requirement of both the second and third BIR domains for the relief of X-linked inhibitor of apoptosis protein (XIAP)-mediated caspase inhibition by Smac.
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12660240 Z.Song, X.Yao, and M.Wu (2003).
Direct interaction between survivin and Smac/DIABLO is essential for the anti-apoptotic activity of survivin during taxol-induced apoptosis.
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11807173 C.D.Bortner, and J.A.Cidlowski (2002).
Cellular mechanisms for the repression of apoptosis.
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12021770 C.L.Holley, M.R.Olson, D.A.Colón-Ramos, and S.Kornbluth (2002).
Reaper eliminates IAP proteins through stimulated IAP degradation and generalized translational inhibition.
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12111795 C.M.Troy, and G.S.Salvesen (2002).
Caspases on the brain.
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12218061 C.R.Arnt, M.V.Chiorean, M.P.Heldebrant, G.J.Gores, and S.H.Kaufmann (2002).
Synthetic Smac/DIABLO peptides enhance the effects of chemotherapeutic agents by binding XIAP and cIAP1 in situ.
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12042762 G.S.Salvesen, and C.S.Duckett (2002).
IAP proteins: blocking the road to death's door.
  Nat Rev Mol Cell Biol, 3, 401-410.  
11852247 H.R.Stennicke, C.A.Ryan, and G.S.Salvesen (2002).
Reprieval from execution: the molecular basis of caspase inhibition.
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12194817 I.Waizenegger, J.F.Giménez-Abián, D.Wernic, and J.M.Peters (2002).
Regulation of human separase by securin binding and autocleavage.
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12120092 J.C.Reed (2002).
Apoptosis-based therapies.
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12450324 J.Salgado, A.J.García-Sáez, G.Malet, I.Mingarro, and E.Pérez-Payá (2002).
Peptides in apoptosis research.
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11927604 J.Silke, C.J.Hawkins, P.G.Ekert, J.Chew, C.L.Day, M.Pakusch, A.M.Verhagen, and D.L.Vaux (2002).
The anti-apoptotic activity of XIAP is retained upon mutation of both the caspase 3- and caspase 9-interacting sites.
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12427028 L.E.Luque, K.P.Grape, and M.Junker (2002).
A highly conserved arginine is critical for the functional folding of inhibitor of apoptosis (IAP) BIR domains.
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12350344 M.Holcik (2002).
The IAP proteins.
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12191471 P.F.Li, J.Li, E.C.Müller, A.Otto, R.Dietz, and R.von Harsdorf (2002).
Phosphorylation by protein kinase CK2: a signaling switch for the caspase-inhibiting protein ARC.
  Mol Cell, 10, 247-258.  
12011074 S.Li, Y.Zhao, X.He, T.H.Kim, D.K.Kuharsky, H.Rabinowich, J.Chen, C.Du, and X.M.Yin (2002).
Relief of extrinsic pathway inhibition by the Bid-dependent mitochondrial release of Smac in Fas-mediated hepatocyte apoptosis.
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11801595 X.M.Sun, S.B.Bratton, M.Butterworth, M.MacFarlane, and G.M.Cohen (2002).
Bcl-2 and Bcl-xL inhibit CD95-mediated apoptosis by preventing mitochondrial release of Smac/DIABLO and subsequent inactivation of X-linked inhibitor-of-apoptosis protein.
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11931755 Y.Shi (2002).
Mechanisms of caspase activation and inhibition during apoptosis.
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12401491 Z.Huang (2002).
The chemical biology of apoptosis. Exploring protein-protein interactions and the life and death of cells with small molecules.
  Chem Biol, 9, 1059-1072.  
  11516343 A.M.Verhagen, E.J.Coulson, and D.L.Vaux (2001).
Inhibitor of apoptosis proteins and their relatives: IAPs and other BIRPs.
  Genome Biol, 2, REVIEWS3009.  
11673685 B.M.Mow, A.L.Blajeski, J.Chandra, and S.H.Kaufmann (2001).
Apoptosis and the response to anticancer therapy.
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11598139 F.Li, D.Zhang, and K.Fujise (2001).
Characterization of fortilin, a novel antiapoptotic protein.
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11581297 J.C.Reed (2001).
The Survivin saga goes in vivo.
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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
11290317 L.Goyal (2001).
Cell death inhibition: keeping caspases in check.
  Cell, 104, 805-808.  
11690616 M.Dubois-Dauphin, Y.Pfister, P.G.Vallet, and A.Savioz (2001).
Prevention of apoptotic neuronal death by controlling procaspases? A point of view.
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11489640 P.Huang, and A.Oliff (2001).
Signaling pathways in apoptosis as potential targets for cancer therapy.
  Trends Cell Biol, 11, 343-348.  
11598496 R.W.Keane, S.Kraydieh, G.Lotocki, O.F.Alonso, P.Aldana, and W.D.Dietrich (2001).
Apoptotic and antiapoptotic mechanisms after traumatic brain injury.
  J Cereb Blood Flow Metab, 21, 1189-1198.  
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
11711663 S.W.Fesik, and Y.Shi (2001).
Structural biology. Controlling the caspases.
  Science, 294, 1477-1478.  
11447297 Y.Suzuki, Y.Nakabayashi, and R.Takahashi (2001).
Ubiquitin-protein ligase activity of X-linked inhibitor of apoptosis protein promotes proteasomal degradation of caspase-3 and enhances its anti-apoptotic effect in Fas-induced cell death.
  Proc Natl Acad Sci U S A, 98, 8662-8667.  
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.