PDBsum entry 1tft

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Apoptosis PDB id
Protein chain
117 a.a. *
* Residue conservation analysis
PDB id:
Name: Apoptosis
Title: Nmr structure of an antagonists of the xiap-caspase-9 interaction complexed to the bir3 domain of xiap
Structure: Baculoviral iap repeat-containing protein 4. Chain: a. Fragment: bir3 of xiap: residues 241-356. Synonym: inhibitor of apoptosis protein 3, x-linked inhibitor of apoptosis protein, x-linked iap, iap-like protein, hilp. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: birc4, api3, iap3, xiap. Expressed in: escherichia coli. Expression_system_taxid: 562.
NMR struc: 1 models
Authors: T.K.Oost,C.Sun,R.C.Armstrong,A.S.Al-Assaad,S.F.Betz, T.L.Deckwerth,S.W.Elmore,R.P.Meadows,E.T.Olejniczak, A.K.Oleksijew,T.Oltersdorf,S.H.Rosenberg,A.R.Shoemaker, H.Zou,S.W.Fesik
Key ref: T.K.Oost et al. (2004). Discovery of potent antagonists of the antiapoptotic protein XIAP for the treatment of cancer. J Med Chem, 47, 4417-4426. PubMed id: 15317454 DOI: 10.1021/jm040037k
27-May-04     Release date:   03-May-05    
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: 10.1021/jm040037k J Med Chem 47:4417-4426 (2004)
PubMed id: 15317454  
Discovery of potent antagonists of the antiapoptotic protein XIAP for the treatment of cancer.
T.K.Oost, C.Sun, R.C.Armstrong, A.S.Al-Assaad, S.F.Betz, T.L.Deckwerth, H.Ding, S.W.Elmore, R.P.Meadows, E.T.Olejniczak, A.Oleksijew, T.Oltersdorf, S.H.Rosenberg, A.R.Shoemaker, K.J.Tomaselli, H.Zou, S.W.Fesik.
Inhibitor of apoptosis (IAP) proteins are overexpressed in many cancers and have been implicated in tumor growth, pathogenesis, and resistance to chemo- or radiotherapy. On the basis of the NMR structure of a SMAC peptide complexed with the BIR3 domain of X-linked IAP (XIAP), a novel series of XIAP antagonists was discovered. The most potent compounds in this series bind to the baculovirus IAP repeat 3 (BIR3) domain of XIAP with single-digit nanomolar affinity and promote cell death in several human cancer cell lines. In a MDA-MB-231 breast cancer mouse xenograft model, these XIAP antagonists inhibited the growth of tumors. Close structural analogues that showed only weak binding to the XIAP-BIR3 domain were inactive in the cellular assays and showed only marginal in vivo activity. Our results are consistent with a mechanism in which ligands for the BIR3 domain of XIAP induce apoptosis by freeing up caspases. The present study validates the BIR3 domain of XIAP as a target and supports the use of small molecule XIAP antagonists as a potential therapy for cancers that overexpress XIAP.

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.
  Nat Rev Drug Discov, 11, 109-124.  
21210296 M.S.Ola, M.Nawaz, and H.Ahsan (2011).
Role of Bcl-2 family proteins and caspases in the regulation of apoptosis.
  Mol Cell Biochem, 351, 41-58.  
20734142 T.S.Griffith, T.A.Kucaba, M.A.O'Donnell, J.Burns, C.Benetatos, M.A.McKinlay, S.Condon, and S.Chunduru (2011).
Sensitization of human bladder tumor cells to TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis with a small molecule IAP antagonist.
  Apoptosis, 16, 13-26.  
20882532 A.Mohr, S.M.Albarenque, L.Deedigan, R.Yu, M.Reidy, S.Fulda, and R.M.Zwacka (2010).
Targeting of XIAP combined with systemic mesenchymal stem cell-mediated delivery of sTRAIL ligand inhibits metastatic growth of pancreatic carcinoma cells.
  Stem Cells, 28, 2109-2120.  
19897582 B.Z.Carter, D.H.Mak, W.D.Schober, E.Koller, C.Pinilla, L.T.Vassilev, J.C.Reed, and M.Andreeff (2010).
Simultaneous activation of p53 and inhibition of XIAP enhance the activation of apoptosis signaling pathways in AML.
  Blood, 115, 306-314.  
20461078 D.Lecis, C.Drago, L.Manzoni, P.Seneci, C.Scolastico, E.Mastrangelo, M.Bolognesi, A.Anichini, H.Kashkar, H.Walczak, and D.Delia (2010).
Novel SMAC-mimetics synergistically stimulate melanoma cell death in combination with TRAIL and Bortezomib.
  Br J Cancer, 102, 1707-1716.  
19904270 E.J.Dean, T.Ward, C.Pinilla, R.Houghten, K.Welsh, G.Makin, M.Ranson, and C.Dive (2010).
A small molecule inhibitor of XIAP induces apoptosis and synergises with vinorelbine and cisplatin in NSCLC.
  Br J Cancer, 102, 97.  
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
20613989 J.Scheper, M.Guerra-Rebollo, G.Sanclimens, A.Moure, I.Masip, D.González-Ruiz, N.Rubio, B.Crosas, O.Meca-Cortés, N.Loukili, V.Plans, A.Morreale, J.Blanco, A.R.Ortiz, A.Messeguer, and T.M.Thomson (2010).
Protein-protein interaction antagonists as novel inhibitors of non-canonical polyubiquitylation.
  PLoS One, 5, e11403.  
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.  
20102336 R.Takamatsu, E.Takeshima, C.Ishikawa, K.Yamamoto, H.Teruya, K.Heuner, F.Higa, J.Fujita, and N.Mori (2010).
Inhibition of Akt/GSK3beta signalling pathway by Legionella pneumophila is involved in induction of T-cell apoptosis.
  Biochem J, 427, 57-67.  
19667203 A.Krieg, R.G.Correa, J.B.Garrison, G.Le Negrate, K.Welsh, Z.Huang, W.T.Knoefel, and J.C.Reed (2009).
XIAP mediates NOD signaling via interaction with RIP2.
  Proc Natl Acad Sci U S A, 106, 14524-14529.  
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.  
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.  
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.  
19036706 M.Fakler, S.Loeder, M.Vogler, K.Schneider, I.Jeremias, K.M.Debatin, and S.Fulda (2009).
Small molecule XIAP inhibitors cooperate with TRAIL to induce apoptosis in childhood acute leukemia cells and overcome Bcl-2-mediated resistance.
  Blood, 113, 1710-1722.  
19021159 M.Orzáez, A.Gortat, L.Mondragón, and E.Pérez-Payá (2009).
Peptides and peptide mimics as modulators of apoptotic pathways.
  ChemMedChem, 4, 146-160.  
19039324 S.Fulda (2009).
Inhibitor of apoptosis proteins in hematological malignancies.
  Leukemia, 23, 467-476.  
19130230 S.Fulda (2009).
Cell death in hematological tumors.
  Apoptosis, 14, 409-423.  
19298593 S.Fulda (2009).
Therapeutic opportunities for counteracting apoptosis resistance in childhood leukaemia.
  Br J Haematol, 145, 441-454.  
  19649204 S.H.Vellanki, A.Grabrucker, S.Liebau, C.Proepper, A.Eramo, V.Braun, T.Boeckers, K.M.Debatin, and S.Fulda (2009).
Small-molecule XIAP inhibitors enhance gamma-irradiation-induced apoptosis in glioblastoma.
  Neoplasia, 11, 743-752.  
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.  
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.  
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.  
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.  
18931692 E.C.LaCasse, D.J.Mahoney, H.H.Cheung, S.Plenchette, S.Baird, and R.G.Korneluk (2008).
IAP-targeted therapies for cancer.
  Oncogene, 27, 6252-6275.  
  19077196 H.A.Harrington, K.L.Ho, S.Ghosh, and K.C.Tung (2008).
Construction and analysis of a modular model of caspase activation in apoptosis.
  Theor Biol Med Model, 5, 26.  
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.  
18407359 J.M.Hallett, A.E.Leitch, N.A.Riley, R.Duffin, C.Haslett, and A.G.Rossi (2008).
Novel pharmacological strategies for driving inflammatory cell apoptosis and enhancing the resolution of inflammation.
  Trends Pharmacol Sci, 29, 250-257.  
18459149 J.Plati, O.Bucur, and R.Khosravi-Far (2008).
Dysregulation of apoptotic signaling in cancer: molecular mechanisms and therapeutic opportunities.
  J Cell Biochem, 104, 1124-1149.  
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.  
18230607 K.Sekine, K.Takubo, R.Kikuchi, M.Nishimoto, M.Kitagawa, F.Abe, K.Nishikawa, T.Tsuruo, and M.Naito (2008).
Small molecules destabilize cIAP1 by activating auto-ubiquitylation.
  J Biol Chem, 283, 8961-8968.  
  18582039 L.L.Chan, M.Pineda, J.T.Heeres, P.J.Hergenrother, and B.T.Cunningham (2008).
A general method for discovering inhibitors of protein-DNA interactions using photonic crystal biosensors.
  ACS Chem Biol, 3, 437-448.  
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.  
18554154 M.Lakshmanan, U.Bughani, S.Duraisamy, M.Diwan, S.Dastidar, and A.Ray (2008).
Molecular targeting of E3 ligases--a therapeutic approach for cancer.
  Expert Opin Ther Targets, 12, 855-870.  
18652674 R.Hamacher, R.M.Schmid, D.Saur, and G.Schneider (2008).
Apoptotic pathways in pancreatic ductal adenocarcinoma.
  Mol Cancer, 7, 64.  
18620520 S.M.Langemeijer, Graaf, and J.H.Jansen (2008).
IAPs as therapeutic targets in haematological malignancies.
  Expert Opin Ther Targets, 12, 981-993.  
18573080 V.N.Uversky, C.J.Oldfield, and A.K.Dunker (2008).
Intrinsically disordered proteins in human diseases: introducing the D2 concept.
  Annu Rev Biophys, 37, 215-246.  
18345031 W.Qi, K.Shakalya, A.Stejskal, A.Goldman, S.Beeck, L.Cooke, and D.Mahadevan (2008).
NSC348884, a nucleophosmin inhibitor disrupts oligomer formation and induces apoptosis in human cancer cells.
  Oncogene, 27, 4210-4220.  
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.  
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
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.  
17573556 A.M.Hunter, E.C.LaCasse, and R.G.Korneluk (2007).
The inhibitors of apoptosis (IAPs) as cancer targets.
  Apoptosis, 12, 1543-1568.  
17032924 D.Chauhan, P.Neri, M.Velankar, K.Podar, T.Hideshima, M.Fulciniti, P.Tassone, N.Raje, C.Mitsiades, N.Mitsiades, P.Richardson, L.Zawel, M.Tran, N.Munshi, and K.C.Anderson (2007).
Targeting mitochondrial factor Smac/DIABLO as therapy for multiple myeloma (MM).
  Blood, 109, 1220-1227.  
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.  
17892425 S.Fulda (2007).
Inhibitor of apoptosis proteins as targets for anticancer therapy.
  Expert Rev Anticancer Ther, 7, 1255-1264.  
17471230 S.Giagkousiklidis, S.H.Vellanki, K.M.Debatin, and S.Fulda (2007).
Sensitization of pancreatic carcinoma cells for gamma-irradiation-induced apoptosis by XIAP inhibition.
  Oncogene, 26, 7006-7016.  
17896835 U.Fischer, K.Janssen, and K.Schulze-Osthoff (2007).
Cutting-edge apoptosis-based therapeutics: a panacea for cancer?
  BioDrugs, 21, 273-297.  
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.  
17009316 D.C.Fry (2006).
Protein-protein interactions as targets for small molecule drug discovery.
  Biopolymers, 84, 535-552.  
16585951 D.H.Gutmann, K.Hunter-Schaedle, and K.M.Shannon (2006).
Harnessing preclinical mouse models to inform human clinical cancer trials.
  J Clin Invest, 116, 847-852.  
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.  
16567363 F.Ortuso, T.Langer, and S.Alcaro (2006).
GBPM: GRID-based pharmacophore model: concept and application studies to protein-protein recognition.
  Bioinformatics, 22, 1449-1455.  
16826219 J.C.Reed (2006).
Drug insight: cancer therapy strategies based on restoration of endogenous cell death mechanisms.
  Nat Clin Pract Oncol, 3, 388-398.  
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.  
17049222 X.W.Meng, S.H.Lee, and S.H.Kaufmann (2006).
Apoptosis in the treatment of cancer: a promise kept?
  Curr Opin Cell Biol, 18, 668-676.  
16925947 Y.Sun (2006).
E3 ubiquitin ligases as cancer targets and biomarkers.
  Neoplasia, 8, 645-654.  
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.  
16283145 D.C.Fry, and L.T.Vassilev (2005).
Targeting protein-protein interactions for cancer therapy.
  J Mol Med, 83, 955-963.  
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.
  Oncogene, 24, 7381-7388.  
15939335 M.Arkin (2005).
Protein-protein interactions and cancer: small molecules going in for the kill.
  Curr Opin Chem Biol, 9, 317-324.  
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.  
16336004 Z.Zhang, M.Li, E.R.Rayburn, D.L.Hill, R.Zhang, and H.Wang (2005).
Oncogenes as novel targets for cancer therapy (part IV): regulators of the cell cycle and apoptosis.
  Am J Pharmacogenomics, 5, 397-407.  
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.