3CLX

Crystal structure of XIAP BIR3 domain in complex with a Smac-mimetic compound, Smac005

3CLX の概要

• エントリーDOI: 10.2210/pdb3clx/pdb
• 関連するPDBエントリー: 1G73 3CM2
• 分子名称: Baculoviral IAP repeat-containing protein 4, ZINC ION, (3S,6S,7S,9aS)-6-{[(2S)-2-aminobutanoyl]amino}-N-(diphenylmethyl)-7-(hydroxymethyl)-5-oxooctahydro-1H-pyrrolo[1,2-a]azepine-3-carboxamide, ... (4 entities in total)
• 機能のキーワード: zinc-finger, apoptosis, cytoplasm, ligase, metal-binding, phosphoprotein, polymorphism, protease inhibitor, thiol protease inhibitor, ubl conjugation, ubl conjugation pathway
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm: P98170
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 61918.66

構造登録者

Milani, M.,Mastrangelo, E.,Cossu, F. (登録日: 2008-03-20, 公開日: 2008-10-28, 最終更新日: 2024-10-30)

主引用文献

Mastrangelo, E.,Cossu, F.,Milani, M.,Sorrentino, G.,Lecis, D.,Delia, D.,Manzoni, L.,Drago, C.,Seneci, P.,Scolastico, C.,Rizzo, V.,Bolognesi, M.
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, 2008

PubMed Abstract: 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.

PubMed: 18851976
DOI: 10.1016/j.jmb.2008.09.064

実験手法

X-RAY DIFFRACTION (2.7 Å)