6exw | pdb_00006exw
Crystal structure of cIAP1-BIR3 in complex with a covalently bound SM
Structural highlights
Function[BIRC2_HUMAN] Multi-functional protein which regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, mitogenic kinase signaling, and cell proliferation, as well as cell invasion and metastasis. Acts as an E3 ubiquitin-protein ligase regulating NF-kappa-B signaling and regulates both canonical and non-canonical NF-kappa-B signaling by acting in opposite directions: acts as a positive regulator of the canonical pathway and suppresses constitutive activation of non-canonical NF-kappa-B signaling. The target proteins for its E3 ubiquitin-protein ligase activity include: RIPK1, RIPK2, RIPK3, RIPK4, CASP3, CASP7, CASP8, TRAF2, DIABLO/SMAC, MAP3K14/NIK, MAP3K5/ASK1, IKBKG/NEMO and MXD1/MAD1. Can also function as an E3 ubiquitin-protein ligase of the NEDD8 conjugation pathway, targeting effector caspases for neddylation and inactivation. Acts as an important regulator of innate immune signaling via regulation of Toll-like receptors (TLRs), Nodlike receptors (NLRs) and RIG-I like receptors (RLRs), collectively referred to as pattern recognition receptors (PRRs). Protects cells from spontaneous formation of the ripoptosome, a large multi-protein complex that has the capability to kill cancer cells in a caspase-dependent and caspase-independent manner. Suppresses ripoptosome formation by ubiquitinating RIPK1 and CASP8. Can stimulate the transcriptional activity of E2F1. Plays a role in the modulation of the cell cycle.[1] [2] [3] [4] [5] Publication Abstract from PubMedIAPs (Inhibitor of Apoptosis Proteins) are highly conserved negative regulators of apoptosis overexpressed in many cancer cells. Based on their endogenous antagonist, Smac/DIABLO, mimic compounds (Smac-mimetics, SMs) have been developed to inhibit IAPs pro-survival activity, showing promising effects in advanced phases of clinical trials. Since different IAP homologues play distinctive roles in cancer cell survival and immunomodulation, SM-induced apoptosis proceeds through diverse mechanisms. After binding to their BIR3 domain, SMs have been shown to rapidly induce auto-ubiquitylation and degradation of cellular IAPs (cIAPs), thus leading to cell death mainly by activation of the non-canonical NF-kappaB pathway. For this reason, we started the BIR3-driven design of compounds selective for cIAP1 and with reduced affinity for X-linked IAP (XIAP), in order to focus SMs anti-tumor activity on cIAPs degradation. In this work, we describe the crystal structures of the BIR3 domains of cIAP1 and XIAP, each in complex with a cIAP1-selective SM (SM130 and SM114, respectively). The two SMs displayed 23- and 32-fold higher affinity for cIAP1-BIR3 over XIAP-BIR3 in molecular displacement experiments based on fluorescence polarization. In vitro cell-based assays confirmed that both selective SMs triggered apoptosis in cancer cells with different efficiencies by inducing caspases-3, -8 and -9-independent cIAP1 degradation. The design of cIAPs-selective compounds represents an innovative approach in the field of anti-cancer drugs development, being useful to elucidate different pro-survival mechanisms, and to reduce the adverse effects of pan-IAPs compounds in cancer therapy. This article is protected by copyright. All rights reserved. Structure-based design and molecular profiling of Smac-mimetics selective for cellular IAPs.,Corti A, Milani M, Lecis D, Seneci P, de Rosa M, Mastrangelo E, Cossu F FEBS J. 2018 Jul 28. doi: 10.1111/febs.14616. PMID:30055105[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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