X-linked inhibitor of apoptosis

Target id: 2790

Nomenclature: X-linked inhibitor of apoptosis

Family: Inhibitors of apoptosis (IAP) protein family

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

   GtoImmuPdb view: OFF :     X-linked inhibitor of apoptosis has curated GtoImmuPdb data

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 497 Xq25 XIAP X-linked inhibitor of apoptosis
Mouse - 496 X A3-A5 Xiap X-linked inhibitor of apoptosis
Rat - 496 Xq11 Xiap X-linked inhibitor of apoptosis
Previous and Unofficial Names
BIRC4 | hILP | API3 | baculoviral IAP repeat-containing 4 | X-linked inhibitor of apoptosis, E3 ubiquitin protein ligase
Database Links
ChEMBL Target
Ensembl Gene
Entrez Gene
GenitoUrinary Development Molecular Anatomy Project
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the complex of XIAP-BIR2 and caspase 3
PDB Id:  1I3O
Resolution:  2.7Å
Species:  Human
References:  14
Image of receptor 3D structure from RCSB PDB
Description:  Fragment-Based Drug Discovery Targeting Inhibitor of Apoptosis Proteins: Compound 4
PDB Id:  5C3K
Ligand:  compound 4 [PMID: 26218264]
Resolution:  2.02Å
Species:  Human
References:  4

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
BV-6 Hs Inhibition 8.9 pKd 16
pKd 8.9 (Kd 1.3x10-9 M) [16]
Description: Assayed using expressed XIAP BIR2-BIR3 domain construct
SM-122 Hs Inhibition 7.6 pKi 13
pKi 7.6 (Ki 2.6x10-8 M) [13]
LCL161 Hs Inhibition 7.5 pIC50 7
pIC50 7.5 (IC50 3x10-8 M) [7]
Description: Assay uses recombinantly expressed BIR3 domain of XIAP
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
birinapant Hs Antagonist 7.3 pKd 1
pKd 7.3 (Kd 4.5x10-8 M) [1]
SM-337 Hs Antagonist 7.6 pKi 13
pKi 7.6 (Ki 2.6x10-8 M) [13]
Description: Fluorescence polarization assay using hXIAP BIR3 domain (residues 241-356)
GDC-0152 Hs Antagonist 7.6 pKi 9
pKi 7.6 (Ki 2.8x10-8 M) [9]
Description: BIR3 domain of hXIAP
AT-406 Hs Antagonist 7.2 pKi 3
pKi 7.2 (Ki 6.64x10-8 M) [3]
Description: Competitive inhibition of human XIAP BIR3 domain expressed in Escherichia coli.
AZD5582 Hs Antagonist 7.8 pIC50 11
pIC50 7.8 (IC50 1.5x10-8 M) [11]
Antagonist Comments
AZD5582 is a peptide mimetic. It consists of a dimeric structure, with sequences based on the AVPI motif of DIABLO (aka Smac; Q9NR28). DIABLO is a peptide of mitochondrial origin and is an endogenous pro-apoptotic antagonist of IAP protein function.
Immunopharmacology Comments
Mouse experiments suggest that XIAP regulates innate immune responses (to Listeria monocytogenes infection) by potentiating synergy between Toll-like receptors (TLRs) and NOD-like receptors (NLRs) through activation of JNK- and NF-κB-dependent signaling [2].
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process ID:  2
Comment: 
GO Annotation:  Associated to GO processes
GO Processes:  regulation of innate immune response (GO:0045088) TAS
regulation of inflammatory response (GO:0050727) TAS
regulation of nucleotide-binding oligomerization domain containing signaling pathway (GO:0070424) TAS
References: 
Immuno Process:  Immune regulation
Immuno Process ID:  6
Comment: 
GO Annotation:  Associated to GO processes
GO Processes:  regulation of innate immune response (GO:0045088) TAS
regulation of inflammatory response (GO:0050727) TAS
regulation of nucleotide-binding oligomerization domain containing signaling pathway (GO:0070424) TAS
References: 
Immuno Process:  Cellular signalling
Immuno Process ID:  11
Comment: 
GO Annotation:  Associated to GO processes
GO Processes:  ubiquitin-protein transferase activity (GO:0004842) IDA
positive regulation of protein ubiquitination (GO:0031398) IDA
ubiquitin protein ligase activity (GO:0061630) EXP
regulation of nucleotide-binding oligomerization domain containing signaling pathway (GO:0070424) TAS
positive regulation of protein linear polyubiquitination (GO:1902530) IDA
References: 
Physiological Consequences of Altering Gene Expression
Xiap null mice have an impaired innate immune control of Listeria monocytogenes infection.
Species:  Mouse
Tissue: 
Technique: 
References:  2
Xiap null mice develop normally and have no overt defect in apoptotic function. They do however, upregulate expression of the related IAPs, cIAP1 and cIAP2, potentially as a compensatory mechanism in the absence of Xiap protein..
Species:  Mouse
Tissue: 
Technique:  Homologous gene targeting
References:  10
Clinically-Relevant Mutations and Pathophysiology
Disease:  Lymphoproliferative syndrome, X-linked, 2; XLP2
Synonyms: Duncan disease
Duncan's syndrome
Lymphoproliferative disease [Disease Ontology: DOID:619]
X-linked lymphoproliferative disease [Orphanet: ORPHA2442]
Disease Ontology: DOID:619
OMIM: 300635
Orphanet: ORPHA2442
General Comments
XIAP binds directly to the key apoptotic proteases, caspase 3, 7 and 9 [6] and may be the only bona fide caspase inhibitor in this protein family [8]. Caspases 3 and 7 are executioner caspases involved in the effector arm of apoptosis [12]. Binding interaction occurs between the BIR2 (second baculovirus IAP repeat) domain of XIAP and the active-site substrate groove of these caspases [8]. The interaction with caspase 9 occurs via the third BIR domain [5,15].

References

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1. Allensworth JL, Sauer SJ, Lyerly HK, Morse MA, Devi GR. (2013) Smac mimetic Birinapant induces apoptosis and enhances TRAIL potency in inflammatory breast cancer cells in an IAP-dependent and TNF-α-independent mechanism. Breast Cancer Res. Treat.137 (2): 359-71. [PMID:23225169]

2. Bauler LD, Duckett CS, O'Riordan MX. (2008) XIAP regulates cytosol-specific innate immunity to Listeria infection. PLoS Pathog.4 (8): e1000142. [PMID:18769721]

3. Cai Q, Sun H, Peng Y, Lu J, Nikolovska-Coleska Z, McEachern D, Liu L, Qiu S, Yang CY, Miller R et al.. (2011) A potent and orally active antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in clinical development for cancer treatment. J. Med. Chem.54 (8): 2714-26. [PMID:21443232]

4. Chessari G, Buck IM, Day JE, Day PJ, Iqbal A, Johnson CN, Lewis EJ, Martins V, Miller D, Reader M et al.. (2015) Fragment-Based Drug Discovery Targeting Inhibitor of Apoptosis Proteins: Discovery of a Non-Alanine Lead Series with Dual Activity Against cIAP1 and XIAP. J. Med. Chem.58 (16): 6574-88. [PMID:26218264]

5. Deveraux QL, Leo E, Stennicke HR, Welsh K, Salvesen GS, Reed JC. (1999) Cleavage of human inhibitor of apoptosis protein XIAP results in fragments with distinct specificities for caspases. EMBO J.18 (19): 5242-51. [PMID:10508158]

6. Deveraux QL, Reed JC. (1999) IAP family proteins--suppressors of apoptosis. Genes Dev.13 (3): 239-52. [PMID:9990849]

7. Donnell AF, Michoud C, Rupert KC, Han X, Aguilar D, Frank KB, Fretland AJ, Gao L, Goggin B, Hogg JH et al.. (2013) Benzazepinones and benzoxazepinones as antagonists of inhibitor of apoptosis proteins (IAPs) selective for the second baculovirus IAP repeat (BIR2) domain. J. Med. Chem.56 (20): 7772-87. [PMID:24083782]

8. Eckelman BP, Salvesen GS, Scott FL. (2006) Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family. EMBO Rep.7 (10): 988-94. [PMID:17016456]

9. Flygare JA, Beresini M, Budha N, Chan H, Chan IT, Cheeti S, Cohen F, Deshayes K, Doerner K, Eckhardt SG et al.. (2012) Discovery of a potent small-molecule antagonist of inhibitor of apoptosis (IAP) proteins and clinical candidate for the treatment of cancer (GDC-0152). J. Med. Chem.55 (9): 4101-13. [PMID:22413863]

10. Harlin H, Reffey SB, Duckett CS, Lindsten T, Thompson CB. (2001) Characterization of XIAP-deficient mice. Mol. Cell. Biol.21 (10): 3604-8. [PMID:11313486]

11. Hennessy EJ, Adam A, Aquila BM, Castriotta LM, Cook D, Hattersley M, Hird AW, Huntington C, Kamhi VM, Laing NM et al.. (2013) Discovery of a novel class of dimeric Smac mimetics as potent IAP antagonists resulting in a clinical candidate for the treatment of cancer (AZD5582). J. Med. Chem.56 (24): 9897-919. [PMID:24320998]

12. Nicholson DW. (1999) Caspase structure, proteolytic substrates, and function during apoptotic cell death. Cell Death Differ.6 (11): 1028-42. [PMID:10578171]

13. Peng Y, Sun H, Nikolovska-Coleska Z, Qiu S, Yang CY, Lu J, Cai Q, Yi H, Kang S, Yang D et al.. (2008) Potent, orally bioavailable diazabicyclic small-molecule mimetics of second mitochondria-derived activator of caspases. J. Med. Chem.51 (24): 8158-62. [PMID:19049347]

14. Riedl SJ, Renatus M, Schwarzenbacher R, Zhou Q, Sun C, Fesik SW, Liddington RC, Salvesen GS. (2001) Structural basis for the inhibition of caspase-3 by XIAP. Cell104 (5): 791-800. [PMID:11257232]

15. Sun C, Cai M, Meadows RP, Xu N, Gunasekera AH, Herrmann J, Wu JC, Fesik SW. (2000) NMR structure and mutagenesis of the third Bir domain of the inhibitor of apoptosis protein XIAP. J. Biol. Chem.275 (43): 33777-81. [PMID:10934209]

16. Varfolomeev E, Blankenship JW, Wayson SM, Fedorova AV, Kayagaki N, Garg P, Zobel K, Dynek JN, Elliott LO, Wallweber HJ et al.. (2007) IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis. Cell131 (4): 669-81. [PMID:18022362]

How to cite this page

Inhibitors of apoptosis (IAP) protein family: X-linked inhibitor of apoptosis. Last modified on 15/02/2017. Accessed on 17/12/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2790.