PDBsum entry 3clx

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protein ligands metals Protein-protein interface(s) links
Ligase, apoptosis PDB id
Protein chains
101 a.a. *
X22 ×6
_ZN ×4
Waters ×46
* Residue conservation analysis
PDB id:
Name: Ligase, apoptosis
Title: Crystal structure of xiap bir3 domain in complex with a smac-mimetic compound, smac005
Structure: Baculoviral iap repeat-containing protein 4. Chain: d, a, b, c. Fragment: unp residues 241-356. Synonym: e3 ubiquitin-protein ligase xiap, 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
2.70Å     R-factor:   0.225     R-free:   0.306
Authors: M.Milani,E.Mastrangelo,F.Cossu
Key ref:
E.Mastrangelo et al. (2008). Targeting the X-linked inhibitor of apoptosis protein through 4-substituted azabicyclo[5.3.0]alkane smac mimetics. Structure, activity, and recognition principles. J Mol Biol, 384, 673-689. PubMed id: 18851976 DOI: 10.1016/j.jmb.2008.09.064
20-Mar-08     Release date:   28-Oct-08    
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Protein chains
Pfam   ArchSchema ?
P98170  (XIAP_HUMAN) -  E3 ubiquitin-protein ligase XIAP
497 a.a.
101 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain


DOI no: 10.1016/j.jmb.2008.09.064 J Mol Biol 384:673-689 (2008)
PubMed id: 18851976  
Targeting the X-linked inhibitor of apoptosis protein through 4-substituted azabicyclo[5.3.0]alkane smac mimetics. Structure, activity, and recognition principles.
E.Mastrangelo, F.Cossu, M.Milani, G.Sorrentino, D.Lecis, D.Delia, L.Manzoni, C.Drago, P.Seneci, C.Scolastico, V.Rizzo, M.Bolognesi.
The X-linked inhibitor of apoptosis protein (XIAP) is overexpressed in several malignant cells where it prevents apoptosis by binding to, and blocking, the activation of caspase-3, -7, and -9. Human XIAP (479 residues) is composed of three tandem-repeated baculoviral IAP repeat (BIR) domains (BIR1-3), and by a C-terminal RING domain. Smac-DIABLO [second mitochondria-derived activator of caspases (Smac)-direct IAP binding protein with low pI (DIABLO)], the natural antagonist of XIAP, binds through its N-terminal sequence AVPI to the same surface groove, in the BIR domains, that binds caspases. Synthetic compounds mimicking such tetrapeptide motif effectively block the interaction between IAP and active caspases, thus triggering apoptosis. Peptidomimetics based on an azabicyclo[x.y.0]alkane scaffolds, have been shown to bind the BIR3 domain of XIAP with micromolar to nanomolar affinities, thus presenting attractive features for drug lead optimization. Here we report a study on three newly synthesized Smac mimetics, which have been characterized in their complexes with XIAP BIR3 domain through X-ray crystallography and molecular modelling/docking simulations. Based on analysis of the crystal structures, we show that specific substitutions at the 4-position of the azabicyclo[5.3.0]alkane scaffold results in sizeable effects on the peptidomimetic-BIR3 domain affinity. By means of functional, biophysical and simulative approaches we also propose that the same Smac mimetics can bind XIAP BIR2 domain at a location structurally related to the BIR3 domain AVPI binding groove. Details of the XIAP-Smac mimetic recognition principles highlighted by this study are discussed in light of the drug-like profile of the three (potentially proapoptotic) compounds developed that show improved performance in ADMET (adsorption, distribution, metabolism, excretion and toxicity) tests.
  Selected figure(s)  
Figure 3.
Fig. 3. (a) Fluorescence polarization saturation curves of the probe used (5 nM) mixed with increasing concentrations of recombinant fpBIR3 bearing an N-terminal (His)[6]-tag. (b) Displacement of the fluorescent probe from fpBIR3 using the unsubstituted Smac001 as matched control and the three 4-substituted azabicyclo[5.3.0]alkane Smac mimetics (Smac005, Smac010, and Smac037).
Figure 6.
Fig. 6. Stereo view of the BIR3–Smac mimetics interaction network. The main residues involved in stabilizing interactions with (a) Smac005 and (b) Smac010 are shown.
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2008, 384, 673-689) copyright 2008.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
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.  
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
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.  
20119528 A.Busca, M.Saxena, M.Kryworuchko, and A.Kumar (2009).
Anti-apoptotic genes in the survival of monocytic cells during infection.
  Curr Genomics, 10, 306-317.  
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