2i3h

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spinqualitylabelsall models 2i3h, resolution 1.62Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Structure of an ML-IAP/XIAP chimera bound to a 4-mer peptide (AVPW)

Overview

Designed second mitochondrial activator of caspases (Smac) mimetics based, on an accessible [7,5]-bicyclic scaffold bind to and antagonize protein, interactions involving the inhibitor of apoptosis (IAP) proteins, X-chromosome-linked IAP (XIAP), melanoma IAP (ML-IAP), and c-IAPs 1 and 2, (cIAP1 and cIAP2). The design rationale is based on a combination of, phage-panning data, peptide binding studies, and a survey of potential, isosteres. The synthesis of two scaffolds is described. These compounds, bind the XIAP-baculoviral IAP repeat 3 (BIR3), cIAP1-BIR3, cIAP2-BIR3, and, ML-IAP-BIR domains with submicromolar affinities. The most potent Smac, mimetic binds the cIAP1-BIR3 and ML-IAP-BIR domains with a K i of 50 nM., The X-ray crystal structure of this compound bound to an ML-IAP/XIAP, chimeric BIR domain protein is compared with that of a complex with a, phage-derived tetrapeptide, AVPW. The structures show that these compounds, bind to the Smac-binding site on ML-IAP with identical hydrogen-bonding, patterns and similar hydrophobic interactions. Consistent with the, structural data, coimmunoprecipitation experiments demonstrate that the, compounds can effectively block Smac interactions with ML-IAP. The, compounds are further demonstrated to activate caspase-3 and -7, to reduce, cell viability in assays using MDA-MB-231 breast cancer cells and A2058, melanoma cells, and to enhance doxorubicin-induced apoptosis in MDA-MB-231, cells.

About this Structure

2I3H is a Single protein structure of sequence from Homo sapiens with ZN, LI, BTB and EDO as ligands. Full crystallographic information is available from OCA.

Reference

Design, synthesis, and biological activity of a potent Smac mimetic that sensitizes cancer cells to apoptosis by antagonizing IAPs., Zobel K, Wang L, Varfolomeev E, Franklin MC, Elliott LO, Wallweber HJ, Okawa DC, Flygare JA, Vucic D, Fairbrother WJ, Deshayes K, ACS Chem Biol. 2006 Sep 19;1(8):525-33. PMID:17168540

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