2I3H

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

Summary for 2I3H

• Entry DOI: 10.2210/pdb2i3h/pdb
• Related: 1OXN 1OXQ 1OY7 1TW6
• Descriptor: Baculoviral IAP repeat-containing protein 7, AVPW peptide, ZINC ION, ... (7 entities in total)
• Functional Keywords: zinc binding, peptide complex, apoptosis inhibition, peptidomimetic, small molecule, drug design, inhibitor-apoptosis complex, inhibitor/apoptosis
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: Q96CA5
• Total number of polymer chains: 4
• Total formula weight: 31369.36

Authors

Fairbrother, W.J.,Franklin, M.C. (deposition date: 2006-08-18, release date: 2006-09-19, Last modification date: 2024-04-03)

Primary citation

Zobel, K.,Wang, L.,Varfolomeev, E.,Franklin, M.C.,Elliott, L.O.,Wallweber, H.J.,Okawa, D.C.,Flygare, J.A.,Vucic, D.,Fairbrother, W.J.,Deshayes, K.
Design, synthesis, and biological activity of a potent Smac mimetic that sensitizes cancer cells to apoptosis by antagonizing IAPs.
Acs Chem.Biol., 1:525-533, 2006

PubMed Abstract: 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.

PubMed: 17168540
DOI: 10.1021/cb600276q

Experimental method

X-RAY DIFFRACTION (1.62 Å)