PDBsum entry 1f9x

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Apoptosis inhibitor PDB id
Protein chain
117 a.a. *
* Residue conservation analysis
PDB id:
Name: Apoptosis inhibitor
Title: Average nmr solution structure of the bir-3 domain of xiap
Structure: Inhibitor of apoptosis protein xiap. Chain: a. Fragment: residues 241-356. Synonym: apoptosis inhibitor 3. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.
NMR struc: 1 models
Authors: C.Sun,M.Cai,R.P.Meadows,S.W.Fesik
Key ref:
C.Sun et al. (2000). NMR structure and mutagenesis of the third Bir domain of the inhibitor of apoptosis protein XIAP. J Biol Chem, 275, 33777-33781. PubMed id: 10934209 DOI: 10.1074/jbc.M006226200
11-Jul-00     Release date:   11-Jul-01    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P98170  (XIAP_HUMAN) -  E3 ubiquitin-protein ligase XIAP
497 a.a.
117 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)


DOI no: 10.1074/jbc.M006226200 J Biol Chem 275:33777-33781 (2000)
PubMed id: 10934209  
NMR structure and mutagenesis of the third Bir domain of the inhibitor of apoptosis protein XIAP.
C.Sun, M.Cai, R.P.Meadows, N.Xu, A.H.Gunasekera, J.Herrmann, J.C.Wu, S.W.Fesik.
The inhibitor of apoptosis proteins (IAPs) regulate the caspase family of cysteine proteases, which play an important role in the execution of programmed cell death. Human X-linked inhibitor of apoptosis protein (XIAP) is a potent inhibitor of caspases-3, -7, and -9. Here we show that the Bir3 domain is the minimal region of XIAP that is needed for potent caspase-9 inhibition. The three-dimensional structure of the Bir3 domain of XIAP, determined by NMR spectroscopy, resembles a classical zinc finger and consists of five alpha-helices, a three-stranded beta-sheet, and a zinc atom chelated to three cysteines and one histidine. The structure of the Bir3 domain is similar to that of the Bir2 domain of XIAP but differs from the previously determined structure of the Bir3 domain of MIHB. Based on site-directed mutagenesis, we have identified the regions of the Bir3 domain of XIAP that are important for inhibiting caspase-9. Despite the structural similarities of the Bir2 and Bir3 domain of XIAP, a different set of residues were found to be critical for inhibiting the individual caspases. These results suggest that XIAP inhibits caspase-3 and caspase-9 in a different manner.
  Selected figure(s)  
Figure 4.
Fig. 4. Ribbon (25) depiction of the structural comparison of the Bir3 domain of XIAP (residues 255-346) (a), the Bir2 domain of XIAP (residues 155-234) (b), and the Bir3 domain of MIHB (residues 268-356) (c). The -helices are shown in red, -sheets in green, zinc in magenta, and the side chains of the residues that chelate zinc are colored yellow.
Figure 6.
Fig. 6. (a) Two views of the electrostatic potential surface of the averaged minimized NMR structure of XIAP () prepared using the GRASP program (26). The red areas correspond to the negatively charged regions, and the blue areas represent the positively charged portions of the protein. (b) Surface representation of the Bir3 domain of XIAP in the same orientation as shown in Fig. 4a. Residues with little effect on caspase-9 inhibition are colored green, whereas those residues that displayed a marked loss in their ability to inhibit caspase-9 (IC[50] > 1 µM) are colored magenta.
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2000, 275, 33777-33781) copyright 2000.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
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.  
19590513 S.Galbán, and C.S.Duckett (2010).
XIAP as a ubiquitin ligase in cellular signaling.
  Cell Death Differ, 17, 54-60.  
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.
  Cell, 141, 859-871.  
19956646 A.Kotevski, W.D.Cook, D.L.Vaux, and B.A.Callus (2009).
Identification of an Xiap-like pseudogene on mouse chromosome 7.
  PLoS One, 4, e8078.  
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.  
19009351 K.Watanabe, C.Ambekar, H.Wang, A.Ciccolini, A.D.Schimmer, and Y.Dror (2009).
SBDS-deficiency results in specific hypersensitivity to Fas stimulation and accumulation of Fas at the plasma membrane.
  Apoptosis, 14, 77-89.  
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.
  Arthritis Rheum, 60, 3476-3484.  
18708583 A.J.Schile, M.García-Fernández, and H.Steller (2008).
Regulation of apoptosis by XIAP ubiquitin-ligase activity.
  Genes Dev, 22, 2256-2266.  
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.  
18485100 J.C.Russell, H.Whiting, N.Szuflita, and M.A.Hossain (2008).
Nuclear translocation of X-linked inhibitor of apoptosis (XIAP) determines cell fate after hypoxia ischemia in neonatal brain.
  J Neurochem, 106, 1357-1370.  
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.  
18786092 M.S.Bhuiyan, and K.Fukunaga (2008).
Activation of HtrA2, a mitochondrial serine protease mediates apoptosis: current knowledge on HtrA2 mediated myocardial ischemia/reperfusion injury.
  Cardiovasc Ther, 26, 224-232.  
18617897 P.Makhov, K.Golovine, R.G.Uzzo, J.Rothman, P.L.Crispen, T.Shaw, B.J.Scoll, and V.M.Kolenko (2008).
Zinc chelation induces rapid depletion of the X-linked inhibitor of apoptosis and sensitizes prostate cancer cells to TRAIL-mediated apoptosis.
  Cell Death Differ, 15, 1745-1751.  
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.  
18439892 S.M.Srinivasula, and J.D.Ashwell (2008).
IAPs: what's in a name?
  Mol Cell, 30, 123-135.  
16946729 B.A.Callus, and D.L.Vaux (2007).
Caspase inhibitors: viral, cellular and chemical.
  Cell Death Differ, 14, 73-78.  
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.  
17097678 M.Sommerhalter, Y.Zhang, and A.C.Rosenzweig (2007).
Solution structure of the COMMD1 N-terminal domain.
  J Mol Biol, 365, 715-721.
PDB code: 2h2m
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
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.  
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.  
16869888 E.Dudich, L.Semenkova, I.Dudich, A.Denesyuk, E.Tatulov, and T.Korpela (2006).
Alpha-fetoprotein antagonizes X-linked inhibitor of apoptosis protein anticaspase activity and disrupts XIAP-caspase interaction.
  FEBS J, 273, 3837-3849.  
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.  
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.  
16212486 N.Yan, and Y.Shi (2005).
Mechanisms of apoptosis through structural biology.
  Annu Rev Cell Dev Biol, 21, 35-56.  
16262685 P.K.Ho, and C.J.Hawkins (2005).
Mammalian initiator apoptotic caspases.
  FEBS J, 272, 5436-5453.  
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.
  Nat Rev Cancer, 5, 876-885.  
15665817 U.Fischer, and K.Schulze-Osthoff (2005).
Apoptosis-based therapies and drug targets.
  Cell Death Differ, 12, 942-961.  
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.  
15161430 M.Holcík (2004).
Targeting endogenous inhibitors of apoptosis for treatment of cancer, stroke and multiple sclerosis.
  Expert Opin Ther Targets, 8, 241-253.  
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
15520809 S.J.Riedl, and Y.Shi (2004).
Molecular mechanisms of caspase regulation during apoptosis.
  Nat Rev Mol Cell Biol, 5, 897-907.  
15029247 Y.Gottfried, A.Rotem, R.Lotan, H.Steller, and S.Larisch (2004).
The mitochondrial ARTS protein promotes apoptosis through targeting XIAP.
  EMBO J, 23, 1627-1635.  
15273300 Y.Shi (2004).
Caspase activation, inhibition, and reactivation: a mechanistic view.
  Protein Sci, 13, 1979-1987.  
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.  
12973017 A.Saito, T.Hayashi, S.Okuno, M.Ferrand-Drake, and P.H.Chan (2003).
Interaction between XIAP and Smac/DIABLO in the mouse brain after transient focal cerebral ischemia.
  J Cereb Blood Flow Metab, 23, 1010-1019.  
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
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.  
14609433 M.Fraser, B.Leung, A.Jahani-Asl, X.Yan, W.E.Thompson, and B.K.Tsang (2003).
Chemoresistance in human ovarian cancer: the role of apoptotic regulators.
  Reprod Biol Endocrinol, 1, 66.  
12565009 M.Los, C.J.Burek, C.Stroh, K.Benedyk, H.Hug, and A.Mackiewicz (2003).
Anticancer drugs of tomorrow: apoptotic pathways as targets for drug design.
  Drug Discov Today, 8, 67-77.  
12815069 Q.H.Yang, R.Church-Hajduk, J.Ren, M.L.Newton, and C.Du (2003).
Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis (IAP) irreversibly inactivates IAPs and facilitates caspase activity in apoptosis.
  Genes Dev, 17, 1487-1496.  
12474256 T.M.Sauerwald, G.A.Oyler, and M.J.Betenbaugh (2003).
Study of caspase inhibitors for limiting death in mammalian cell culture.
  Biotechnol Bioeng, 81, 329-340.  
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.
  Trends Biochem Sci, 27, 94.  
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.
  J Cell Biol, 157, 115-124.  
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.
  Biochemistry, 41, 13663-13671.  
12115719 L.Ravagnan, T.Roumier, and G.Kroemer (2002).
Mitochondria, the killer organelles and their weapons.
  J Cell Physiol, 192, 131-137.  
11807766 T.M.Sauerwald, M.J.Betenbaugh, and G.A.Oyler (2002).
Inhibiting apoptosis in mammalian cell culture using the caspase inhibitor XIAP and deletion mutants.
  Biotechnol Bioeng, 77, 704-716.  
  12163389 V.Poulaki, C.S.Mitsiades, V.Kotoula, S.Tseleni-Balafouta, A.Ashkenazi, D.A.Koutras, and N.Mitsiades (2002).
Regulation of Apo2L/tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in thyroid carcinoma cells.
  Am J Pathol, 161, 643-654.  
11931755 Y.Shi (2002).
Mechanisms of caspase activation and inhibition during apoptosis.
  Mol Cell, 9, 459-470.  
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.  
11313486 H.Harlin, S.B.Reffey, C.S.Duckett, T.Lindsten, and C.B.Thompson (2001).
Characterization of XIAP-deficient mice.
  Mol Cell Biol, 21, 3604-3608.  
11179890 J.H.Laity, B.M.Lee, and P.E.Wright (2001).
Zinc finger proteins: new insights into structural and functional diversity.
  Curr Opin Struct Biol, 11, 39-46.  
11406588 J.Silke, P.G.Ekert, C.L.Day, C.J.Hawkins, M.Baca, J.Chew, M.Pakusch, A.M.Verhagen, and D.L.Vaux (2001).
Direct inhibition of caspase 3 is dispensable for the anti-apoptotic activity of XIAP.
  EMBO J, 20, 3114-3123.  
11511363 J.W.Wu, A.E.Cocina, J.Chai, B.A.Hay, and Y.Shi (2001).
Structural analysis of a functional DIAP1 fragment bound to grim and hid peptides.
  Mol Cell, 8, 95.
PDB codes: 1jd4 1jd5 1jd6
11290317 L.Goyal (2001).
Cell death inhibition: keeping caspases in check.
  Cell, 104, 805-808.  
11157976 P.G.Ekert, J.Silke, C.J.Hawkins, A.M.Verhagen, and D.L.Vaux (2001).
DIABLO promotes apoptosis by removing MIHA/XIAP from processed caspase 9.
  J Cell Biol, 152, 483-490.  
11395159 S.B.Bratton, and G.M.Cohen (2001).
Apoptotic death sensor: an organelle's alter ego?
  Trends Pharmacol Sci, 22, 306-315.  
11230124 S.B.Bratton, G.Walker, S.M.Srinivasula, X.M.Sun, M.Butterworth, E.S.Alnemri, and G.M.Cohen (2001).
Recruitment, activation and retention of caspases-9 and -3 by Apaf-1 apoptosome and associated XIAP complexes.
  EMBO J, 20, 998.  
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
11711663 S.W.Fesik, and Y.Shi (2001).
Structural biology. Controlling the caspases.
  Science, 294, 1477-1478.  
  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
11583623 Y.Suzuki, Y.Imai, H.Nakayama, K.Takahashi, K.Takio, and R.Takahashi (2001).
A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death.
  Mol Cell, 8, 613-621.  
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 code is shown on the right.