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PDBsum entry 1nw9

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protein metals Protein-protein interface(s) links
Apoptosis PDB id
1nw9
Jmol
Contents
Protein chains
91 a.a. *
238 a.a. *
Metals
_ZN
* Residue conservation analysis
PDB id:
1nw9
Name: Apoptosis
Title: Structure of caspase-9 in an inhibitory complex with xiap- bir3
Structure: Baculoviral iap repeat-containing protein 4. Chain: a. Synonym: inhibitor of apoptosis protein 3, x-linked inhibitor of apoptosis protein, x-linked iap, iap-like protein, hilp, the bir3 domain of xiap. Engineered: yes. Caspase 9, apoptosis-related cysteine protease. Chain: b. Synonym: catalytic domain of caspase-9.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: birc4 or api3 or iap3 or xiap. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_taxid: 562
Biol. unit: Dimer (from PQS)
Resolution:
2.40Å     R-factor:   0.230     R-free:   0.235
Authors: E.N.Shiozaki,J.Chai,D.J.Rigotti,S.J.Riedl,P.Li, S.M.Srinivasula,E.S.Alnemri,R.Fairman,Y.Shi
Key ref:
E.N.Shiozaki et al. (2003). Mechanism of XIAP-mediated inhibition of caspase-9. Mol Cell, 11, 519-527. PubMed id: 12620238 DOI: 10.1016/S1097-2765(03)00054-6
Date:
05-Feb-03     Release date:   25-Mar-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P98170  (XIAP_HUMAN) -  E3 ubiquitin-protein ligase XIAP
Seq:
Struc:
497 a.a.
91 a.a.
Protein chain
Pfam   ArchSchema ?
P55211  (CASP9_HUMAN) -  Caspase-9
Seq:
Struc:
416 a.a.
238 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: Chain B: E.C.3.4.22.62  - Caspase-9.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     apoptotic process   2 terms 
  Biochemical function     cysteine-type peptidase activity     2 terms  

 

 
DOI no: 10.1016/S1097-2765(03)00054-6 Mol Cell 11:519-527 (2003)
PubMed id: 12620238  
 
 
Mechanism of XIAP-mediated inhibition of caspase-9.
E.N.Shiozaki, J.Chai, D.J.Rigotti, S.J.Riedl, P.Li, S.M.Srinivasula, E.S.Alnemri, R.Fairman, Y.Shi.
 
  ABSTRACT  
 
The inhibitor of apoptosis (IAP) proteins potently inhibit the catalytic activity of caspases. While profound insight into the inhibition of the effector caspases has been gained in recent years, the mechanism of how the initiator caspase-9 is regulated by IAPs remains enigmatic. This paper reports the crystal structure of caspase-9 in an inhibitory complex with the third baculoviral IAP repeat (BIR3) of XIAP at 2.4 A resolution. The structure reveals that the BIR3 domain forms a heterodimer with a caspase-9 monomer. Strikingly, the surface of caspase-9 that interacts with BIR3 also mediates its homodimerization. We demonstrate that monomeric caspase-9 is catalytically inactive due to the absence of a supporting sequence element that could be provided by homodimerization. Thus, XIAP sequesters caspase-9 in a monomeric state, which serves to prevent catalytic activity. These studies, in conjunction with other observations, define a unified mechanism for the activation of all caspases.
 
  Selected figure(s)  
 
Figure 3.
Figure 3. Recognition of Caspase-9 by the BIR3 Domain of XIAP(A) An overall view on the structure of the complex. Caspase-9 and BIR3 are shown as blue and green coil, respectively. A number of critical interface residues from caspase-9 and BIR3 are colored yellow and purple, respectively. To illustrate the complementary binding, the transparent surface contour of caspase-9 is shown.(B) A stereo view on the interface centered around Pro325 and Gly326 of XIAP. The overall coloring scheme is the same as in Figure 1. The side chains from key residues in caspase-9 and XIAP-BIR3 are colored yellow and gold, respectively. Hydrogen bonds are represented by red dashed lines.(C) A stereo view on the interface centered around His343 and Leu344 of XIAP. The side chain of His343 makes two hydrogen bonds to bridge caspase-9 and BIR3 whereas Leu344 packs against multiple hydrophobic residues in caspase-9.(D) A stereo depiction on the recognition of BIR3 by the N-terminal IAP binding motif of caspase-9. The tetrapeptide motif (Ala316-Thr317-Pro318-Phe319) binds to the conserved surface of BIR3 as predicted (Srinivasula et al., 2001). This binding is augmented by the close packing interactions from Pro336 and Pro338 of caspase-9.(E) Functional consequence of point mutations on critical residues of XIAP-BIR3. Cleavage of the procaspase-3 substrate by caspase-9 was performed in the absence or presence of various XIAP-BIR3 point mutants. The results were visualized by SDS-PAGE followed by Coomassie blue staining. The generation and purification of caspase-9 and XIAP-BIR3 mutant proteins and the caspase-9 assay are described in the Experimental Procedures. The procaspase-3 (C163A) precursor was used as the substrate.
Figure 5.
Figure 5. A Schematic Diagram of Caspase-9 Activation and InhibitionThe full-length caspase-9 is colored green, with the prodomain (CARD) shown as a circle. The thickness of the black arrows indicates the preference of the equilibrium. Caspase-9 can be activated by the apoptosome comprising Apaf-1, cytochrome c, and the critical cofactor dATP/ATP. Both isolated caspase-9 and the apoptosome-activated caspase-9 are subject to XIAP-mediated inhibition. See text for a detailed discussion.
 
  The above figures are reprinted by permission from Cell Press: Mol Cell (2003, 11, 519-527) copyright 2003.  
  Figures were selected by an automated process.  

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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20942802 D.Boucher, V.Blais, M.Drag, and J.B.Denault (2011).
Molecular determinants involved in activation of caspase 7.
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21284734 F.Chang-Qing, L.Yi, W.DE-Guang, S.Qing-Bin, H.Xiang-Min, T.Na, and L.Jian-Hua (2011).
Immune clearance gastric carcinoma cells in ascites by activating caspase-9-induced apoptosis.
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21213247 P.L.Kastritis, I.H.Moal, H.Hwang, Z.Weng, P.A.Bates, A.M.Bonvin, and J.Janin (2011).
A structure-based benchmark for protein-protein binding affinity.
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21279667 X.Zhao, T.Laver, S.W.Hong, G.B.Twitty, A.Devos, M.Devos, E.N.Benveniste, and S.E.Nozell (2011).
An NF-κB p65-cIAP2 link is necessary for mediating resistance to TNF-α induced cell death in gliomas.
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20705815 A.E.Kelly, C.Ghenoiu, J.Z.Xue, C.Zierhut, H.Kimura, and H.Funabiki (2010).
Survivin reads phosphorylated histone H3 threonine 3 to activate the mitotic kinase Aurora B.
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20660790 A.H.Filipovich, K.Zhang, A.L.Snow, and R.A.Marsh (2010).
X-linked lymphoproliferative syndromes: brothers or distant cousins?
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21053238 C.J.Farady, and C.S.Craik (2010).
Mechanisms of macromolecular protease inhibitors.
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20704571 D.C.Altieri (2010).
Survivin and IAP proteins in cell-death mechanisms.
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20022954 D.Zhai, E.Yu, C.Jin, K.Welsh, C.W.Shiau, L.Chen, G.S.Salvesen, R.Liddington, and J.C.Reed (2010).
Vaccinia virus protein F1L is a caspase-9 inhibitor.
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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
20198502 F.Van Herreweghe, N.Festjens, W.Declercq, and P.Vandenabeele (2010).
Tumor necrosis factor-mediated cell death: to break or to burst, that's the question.
  Cell Mol Life Sci, 67, 1567-1579.  
19911273 J.Liu, D.Han, Y.Li, L.Zheng, C.Gu, Z.Piao, W.W.Au, X.Xu, and X.Huo (2010).
Lead affects apoptosis and related gene XIAP and Smac expression in the hippocampus of developing rats.
  Neurochem Res, 35, 473-479.  
20221856 M.Assayag, G.Gerstenblith, M.D.Stern, and M.Horowitz (2010).
Long- but not short-term heat acclimation produces an apoptosis-resistant cardiac phenotype: a lesson from heat stress and ischemic/reperfusion insults.
  Cell Stress Chaperones, 15, 651-664.  
20651737 M.Gyrd-Hansen, and P.Meier (2010).
IAPs: from caspase inhibitors to modulators of NF-kappaB, inflammation and cancer.
  Nat Rev Cancer, 10, 561-574.  
20123744 N.T.Ross, W.P.Katt, and A.D.Hamilton (2010).
Synthetic mimetics of protein secondary structure domains.
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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.
  Cell Death Differ, 17, 46-53.  
20134429 Q.P.Peterson, D.R.Goode, D.C.West, R.C.Botham, and P.J.Hergenrother (2010).
Preparation of the caspase-3/7 substrate Ac-DEVD-pNA by solution-phase peptide synthesis.
  Nat Protoc, 5, 294-302.  
20148665 R.S.Whelan, V.Kaplinskiy, and R.N.Kitsis (2010).
Cell death in the pathogenesis of heart disease: mechanisms and significance.
  Annu Rev Physiol, 72, 19-44.  
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.
  Chem Biol Drug Des, 74, 212-223.  
19854829 E.Varfolomeev, B.Alicke, J.M.Elliott, K.Zobel, K.West, H.Wong, J.M.Scheer, A.Ashkenazi, S.E.Gould, W.J.Fairbrother, and D.Vucic (2009).
X chromosome-linked inhibitor of apoptosis regulates cell death induction by proapoptotic receptor agonists.
  J Biol Chem, 284, 34553-34560.  
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.
  Neurosci Lett, 461, 49-53.  
19416807 J.W.Yu, P.D.Jeffrey, and Y.Shi (2009).
Mechanism of procaspase-8 activation by c-FLIPL.
  Proc Natl Acad Sci U S A, 106, 8169-8174.
PDB codes: 3h11 3h13
19034449 K.Connolly, R.Mitter, M.Muir, D.Jodrell, and S.Guichard (2009).
Stable XIAP knockdown clones of HCT116 colon cancer cells are more sensitive to TRAIL, taxanes and irradiation in vitro.
  Cancer Chemother Pharmacol, 64, 307-316.  
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.  
19418469 L.Kleinberg, and B.Davidson (2009).
Cell survival and apoptosis-related molecules in cancer cells in effusions: a comprehensive review.
  Diagn Cytopathol, 37, 613-624.  
19850458 M.Bader, and H.Steller (2009).
Regulation of cell death by the ubiquitin-proteasome system.
  Curr Opin Cell Biol, 21, 878-884.  
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
  20209078 Q.He, J.Shi, S.Jones, J.An, Y.Liu, Y.Huang, and M.S.Sheikh (2009).
Smac deficiency affects endoplasmic reticulum stress-induced apoptosis in human colon cancer cells.
  Mol Cell Pharmacol, 1, 23-28.  
19281821 Q.P.Peterson, D.R.Goode, D.C.West, K.N.Ramsey, J.J.Lee, and P.J.Hergenrother (2009).
PAC-1 activates procaspase-3 in vitro through relief of zinc-mediated inhibition.
  J Mol Biol, 388, 144-158.  
19029953 R.B.Hamanaka, E.Bobrovnikova-Marjon, X.Ji, S.A.Liebhaber, and J.A.Diehl (2009).
PERK-dependent regulation of IAP translation during ER stress.
  Oncogene, 28, 910-920.  
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
19039324 S.Fulda (2009).
Inhibitor of apoptosis proteins in hematological malignancies.
  Leukemia, 23, 467-476.  
19298593 S.Fulda (2009).
Therapeutic opportunities for counteracting apoptosis resistance in childhood leukaemia.
  Br J Haematol, 145, 441-454.  
19233849 S.N.Shelton, M.E.Shawgo, and J.D.Robertson (2009).
Cleavage of Bid by Executioner Caspases Mediates Feed Forward Amplification of Mitochondrial Outer Membrane Permeabilization during Genotoxic Stress-induced Apoptosis in Jurkat Cells.
  J Biol Chem, 284, 11247-11255.  
  19570023 T.West, M.Stump, G.Lodygensky, J.J.Neil, M.Deshmukh, and D.M.Holtzman (2009).
Lack of X-linked inhibitor of apoptosis protein leads to increased apoptosis and tissue loss following neonatal brain injury.
  ASN Neuro, 1, 0.  
19619456 T.Zhang, P.Brazhnik, and J.J.Tyson (2009).
Computational analysis of dynamical responses to the intrinsic pathway of programmed cell death.
  Biophys J, 97, 415-434.  
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
19138149 W.Sun, Z.Nikolovska-Coleska, D.Qin, H.Sun, C.Y.Yang, L.Bai, S.Qiu, Y.Wang, D.Ma, and S.Wang (2009).
Design, synthesis, and evaluation of potent, nonpeptidic mimetics of second mitochondria-derived activator of caspases.
  J Med Chem, 52, 593-596.  
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.  
18055514 A.Dhanasekaran, S.K.Gruenloh, J.N.Buonaccorsi, R.Zhang, G.J.Gross, J.R.Falck, P.K.Patel, E.R.Jacobs, and M.Medhora (2008).
Multiple antiapoptotic targets of the PI3K/Akt survival pathway are activated by epoxyeicosatrienoic acids to protect cardiomyocytes from hypoxia/anoxia.
  Am J Physiol Heart Circ Physiol, 294, H724-H735.  
18708583 A.J.Schile, M.García-Fernández, and H.Steller (2008).
Regulation of apoptosis by XIAP ubiquitin-ligase activity.
  Genes Dev, 22, 2256-2266.  
19012392 B.Zhang, Z.Nikolovska-Coleska, Y.Zhang, L.Bai, S.Qiu, C.Y.Yang, H.Sun, S.Wang, and Y.Wu (2008).
Design, synthesis, and evaluation of tricyclic, conformationally constrained small-molecule mimetics of second mitochondria-derived activator of caspases.
  J Med Chem, 51, 7352-7355.  
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
  18822137 G.Martinez-Ruiz, V.Maldonado, G.Ceballos-Cancino, J.P.Grajeda, and J.Melendez-Zajgla (2008).
Role of Smac/DIABLO in cancer progression.
  J Exp Clin Cancer Res, 27, 48.  
18954041 H.Sun, J.A.Stuckey, Z.Nikolovska-Coleska, D.Qin, J.L.Meagher, S.Qiu, J.Lu, C.Y.Yang, N.G.Saito, and S.Wang (2008).
Structure-based design, synthesis, evaluation, and crystallographic studies of conformationally constrained Smac mimetics as inhibitors of the X-linked inhibitor of apoptosis protein (XIAP).
  J Med Chem, 51, 7169-7180.
PDB code: 2jk7
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.  
18956862 J.W.Huang, Z.Zhang, B.Wu, J.F.Cellitti, X.Zhang, R.Dahl, C.W.Shiau, K.Welsh, A.Emdadi, J.L.Stebbins, J.C.Reed, and M.Pellecchia (2008).
Fragment-based design of small molecule X-linked inhibitor of apoptosis protein inhibitors.
  J Med Chem, 51, 7111-7118.  
18548102 L.Schyschka, A.Rudy, I.Jeremias, N.Barth, G.R.Pettit, and A.M.Vollmar (2008).
Spongistatin 1: a new chemosensitizing marine compound that degrades XIAP.
  Leukemia, 22, 1737-1745.  
18927073 M.E.Shawgo, S.N.Shelton, and J.D.Robertson (2008).
Caspase-mediated Bak Activation and Cytochrome c Release during Intrinsic Apoptotic Cell Death in Jurkat Cells.
  J Biol Chem, 283, 35532-35538.  
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.  
19021141 P.Hauske, C.Ottmann, M.Meltzer, M.Ehrmann, and M.Kaiser (2008).
Allosteric regulation of proteases.
  Chembiochem, 9, 2920-2928.  
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, A.O.de Graaf, and J.H.Jansen (2008).
IAPs as therapeutic targets in haematological malignancies.
  Expert Opin Ther Targets, 12, 981-993.  
19049347 Y.Peng, H.Sun, Z.Nikolovska-Coleska, S.Qiu, C.Y.Yang, J.Lu, Q.Cai, H.Yi, S.Kang, D.Yang, and S.Wang (2008).
Potent, orally bioavailable diazabicyclic small-molecule mimetics of second mitochondria-derived activator of caspases.
  J Med Chem, 51, 8158-8162.  
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.  
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.  
17573556 A.M.Hunter, E.C.LaCasse, and R.G.Korneluk (2007).
The inhibitors of apoptosis (IAPs) as cancer targets.
  Apoptosis, 12, 1543-1568.  
17562856 A.T.Ho, Q.H.Li, H.Okada, T.W.Mak, and E.Zacksenhaus (2007).
XIAP activity dictates Apaf-1 dependency for caspase 9 activation.
  Mol Cell Biol, 27, 5673-5685.  
17339366 C.A.Karikari, I.Roy, E.Tryggestad, G.Feldmann, C.Pinilla, K.Welsh, J.C.Reed, E.P.Armour, J.Wong, J.Herman, D.Rakheja, and A.Maitra (2007).
Targeting the apoptotic machinery in pancreatic cancers using small-molecule antagonists of the X-linked inhibitor of apoptosis protein.
  Mol Cancer Ther, 6, 957-966.  
18028010 E.J.Dean, M.Ranson, F.Blackhall, and C.Dive (2007).
X-linked inhibitor of apoptosis protein as a therapeutic target.
  Expert Opin Ther Targets, 11, 1459-1471.  
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.  
17488476 I.A.Voutsadakis (2007).
Pathogenesis of colorectal carcinoma and therapeutic implications: the roles of the ubiquitin-proteasome system and Cox-2.
  J Cell Mol Med, 11, 252-285.  
17082814 J.C.Timmer, and G.S.Salvesen (2007).
Caspase substrates.
  Cell Death Differ, 14, 66-72.  
17008917 J.Greenwood, and J.Gautier (2007).
XLX is an IAP family member regulated by phosphorylation during meiosis.
  Cell Death Differ, 14, 559-567.  
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.  
16932756 K.M.Wright, A.E.Vaughn, and M.Deshmukh (2007).
Apoptosome dependent caspase-3 activation pathway is non-redundant and necessary for apoptosis in sympathetic neurons.
  Cell Death Differ, 14, 625-633.  
17167759 L.Kleinberg, V.A.Flørenes, I.Silins, K.Haug, C.G.Trope, J.M.Nesland, and B.Davidson (2007).
Nuclear expression of survivin is associated with improved survival in metastatic ovarian carcinoma.
  Cancer, 109, 228-238.  
  17497287 L.Ye, J.Qi, G.Li, D.Tao, and S.Song (2007).
The effect of HBx gene on the apoptosis of hepatic cells.
  J Huazhong Univ Sci Technolog Med Sci, 27, 167-169.  
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
17613437 M.S.Ricci, S.H.Kim, K.Ogi, J.P.Plastaras, J.Ling, W.Wang, Z.Jin, Y.Y.Liu, D.T.Dicker, P.J.Chiao, K.T.Flaherty, C.D.Smith, and W.S.El-Deiry (2007).
Reduction of TRAIL-induced Mcl-1 and cIAP2 by c-Myc or sorafenib sensitizes resistant human cancer cells to TRAIL-induced death.
  Cancer Cell, 12, 66-80.  
17485304 P.Saikumar, M.Mikhailova, and S.L.Pandeswara (2007).
Regulation of caspase-9 activity by differential binding to the apoptosome complex.
  Front Biosci, 12, 3343-3354.  
16977332 Q.Bao, and Y.Shi (2007).
Apoptosome: a platform for the activation of initiator caspases.
  Cell Death Differ, 14, 56-65.  
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.  
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.  
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.
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16339151 B.P.Eckelman, and G.S.Salvesen (2006).
The human anti-apoptotic proteins cIAP1 and cIAP2 bind but do not inhibit caspases.
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16955069 B.Turk (2006).
Targeting proteases: successes, failures and future prospects.
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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.  
16231180 E.Krepela, J.Procházka, P.Fiala, P.Zatloukal, and P.Selinger (2006).
Expression of apoptosome pathway-related transcripts in non-small cell lung cancer.
  J Cancer Res Clin Oncol, 132, 57-68.  
16891304 E.Varfolomeev, S.M.Wayson, V.M.Dixit, W.J.Fairbrother, and D.Vucic (2006).
The inhibitor of apoptosis protein fusion c-IAP2.MALT1 stimulates NF-kappaB activation independently of TRAF1 AND TRAF2.
  J Biol Chem, 281, 29022-29029.  
16339882 E.Z.Bagci, Y.Vodovotz, T.R.Billiar, G.B.Ermentrout, and I.Bahar (2006).
Bistability in apoptosis: roles of bax, bcl-2, and mitochondrial permeability transition pores.
  Biophys J, 90, 1546-1559.  
16931776 L.P.Mueller, J.Luetzkendorf, T.Mueller, K.Reichelt, H.Simon, and H.J.Schmoll (2006).
Presence of mesenchymal stem cells in human bone marrow after exposure to chemotherapy: evidence of resistance to apoptosis induction.
  Stem Cells, 24, 2753-2765.  
16446367 N.Yan, J.R.Huh, V.Schirf, B.Demeler, B.A.Hay, and Y.Shi (2006).
Structure and activation mechanism of the Drosophila initiator caspase Dronc.
  J Biol Chem, 281, 8667-8674.
PDB code: 2fp3
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.  
16341821 Y.Zhang, Y.Wang, W.Gao, R.Zhang, X.Han, M.Jia, and W.Guan (2006).
Transfer of siRNA against XIAP induces apoptosis and reduces tumor cells growth potential in human breast cancer in vitro and in vivo.
  Breast Cancer Res Treat, 96, 267-277.  
15887267 C.Hitz, D.Vogt-Weisenhorn, P.Ruiz, W.Wurst, and T.Floss (2005).
Progressive loss of the spongiotrophoblast layer of Birc6/Bruce mutants results in embryonic lethality.
  Genesis, 42, 91.  
16200201 C.W.Wright, and C.S.Duckett (2005).
Reawakening the cellular death program in neoplasia through the therapeutic blockade of IAP function.
  J Clin Invest, 115, 2673-2678.  
15657060 D.Raina, P.Pandey, R.Ahmad, A.Bharti, J.Ren, S.Kharbanda, R.Weichselbaum, and D.Kufe (2005).
c-Abl tyrosine kinase regulates caspase-9 autocleavage in the apoptotic response to DNA damage.
  J Biol Chem, 280, 11147-11151.  
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.
  EMBO J, 24, 645-655.  
16212486 N.Yan, and Y.Shi (2005).
Mechanisms of apoptosis through structural biology.
  Annu Rev Cell Dev Biol, 21, 35-56.  
15797833 P.Cashio, T.V.Lee, and A.Bergmann (2005).
Genetic control of programmed cell death in Drosophila melanogaster.
  Semin Cell Dev Biol, 16, 225-235.  
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.
  J Virol, 79, 3684-3691.  
  15765138 R.S.Foo, K.Mani, and R.N.Kitsis (2005).
Death begets failure in the heart.
  J Clin Invest, 115, 565-571.  
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.
  Nat Cell Biol, 7, 70-77.  
15941357 Y.Chao, E.N.Shiozaki, S.M.Srinivasula, D.J.Rigotti, R.Fairman, and Y.Shi (2005).
Engineering a dimeric caspase-9: a re-evaluation of the induced proximity model for caspase activation.
  PLoS Biol, 3, e183.
PDB code: 2ar9
15114336 B.A.Schreader, and J.R.Nambu (2004).
A fine balance for life and death decisions.
  Nat Struct Mol Biol, 11, 386-388.  
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
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.
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15101558 E.Krepela, J.Procházka, X.Liul, P.Fiala, and Z.Kinkor (2004).
Increased expression of Apaf-1 and procaspase-3 and the functionality of intrinsic apoptosis apparatus in non-small cell lung carcinoma.
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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
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.
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15280366 J.Davoodi, L.Lin, J.Kelly, P.Liston, and A.E.MacKenzie (2004).
Neuronal apoptosis-inhibitory protein does not interact with Smac and requires ATP to bind caspase-9.
  J Biol Chem, 279, 40622-40628.  
14970175 M.Alvarado-Kristensson, F.Melander, K.Leandersson, L.Rönnstrand, C.Wernstedt, and T.Andersson (2004).
p38-MAPK signals survival by phosphorylation of caspase-8 and caspase-3 in human neutrophils.
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15576038 M.D.Tibbetts, E.N.Shiozaki, L.Gu, E.R.McDonald, W.S.El-Deiry, and Y.Shi (2004).
Crystal structure of a FYVE-type zinc finger domain from the caspase regulator CARP2.
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PDB code: 1y02
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
15542838 P.B.Deming, Z.T.Schafer, J.S.Tashker, M.B.Potts, M.Deshmukh, and S.Kornbluth (2004).
Bcr-Abl-mediated protection from apoptosis downstream of mitochondrial cytochrome c release.
  Mol Cell Biol, 24, 10289-10299.  
15520809 S.J.Riedl, and Y.Shi (2004).
Molecular mechanisms of caspase regulation during apoptosis.
  Nat Rev Mol Cell Biol, 5, 897-907.  
14765125 X.B.Qiu, S.L.Markant, J.Yuan, and A.L.Goldberg (2004).
Nrdp1-mediated degradation of the gigantic IAP, BRUCE, is a novel pathway for triggering apoptosis.
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15189137 X.Jiang, and X.Wang (2004).
Cytochrome C-mediated apoptosis.
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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.
  Mol Cell, 15, 901-912.  
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.
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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.
  Curr Opin Cell Biol, 15, 717-724.  
14517550 J.Chai, N.Yan, J.R.Huh, J.W.Wu, W.Li, B.A.Hay, and Y.Shi (2003).
Molecular mechanism of Reaper-Grim-Hid-mediated suppression of DIAP1-dependent Dronc ubiquitination.
  Nat Struct Biol, 10, 892-898.
PDB code: 1q4q
12906772 J.M.Puck, and S.Zhu (2003).
Immune disorders caused by defects in the caspase cascade.
  Curr Allergy Asthma Rep, 3, 378-384.  
13679576 P.L.Howard, M.C.Chia, S.Del Rizzo, F.F.Liu, and T.Pawson (2003).
Redirecting tyrosine kinase signaling to an apoptotic caspase pathway through chimeric adaptor proteins.
  Proc Natl Acad Sci U S A, 100, 11267-11272.  
14512414 Y.Huang, R.L.Rich, D.G.Myszka, and H.Wu (2003).
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.
  J Biol Chem, 278, 49517-49522.  
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.