| Structural highlights
4mu7 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , |
| Related: | 4mti |
| Gene: | API1, BIRC2, IAP2, MIHB, RNF48 (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
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 PubMed
We previously reported octahydropyrrolo[1,2-a]pyrazine derivative 2 (T-3256336) as a potent antagonist for inhibitors of apoptosis (IAP) proteins. Because compound 2 was susceptible to MDR1 mediated efflux, we developed another scaffold, hexahydropyrazino[1,2-a]indole, using structure-based drug design. The fused benzene ring of this scaffold was aimed at increasing the lipophilicity and decreasing the basicity of the scaffold to improve the membrane permeability across MDR1 expressing cells. We established a chiral pool synthetic route to yield the desired tricyclic chiral isomers. Chemical modification of the core scaffold led to a representative compound 50, which showed strong inhibition of IAP binding (X chromosome-linked IAP [XIAP]: IC50 23nM and cellular IAP [cIAP]: IC50 1.1nM) and cell growth inhibition (MDA-MB-231 cells: GI50 2.8nM) with high permeability and low potential of MDR1 substrate.
Design, synthesis, and biological activities of novel hexahydropyrazino[1,2-a]indole derivatives as potent inhibitors of apoptosis (IAP) proteins antagonists with improved membrane permeability across MDR1 expressing cells.,Shiokawa Z, Hashimoto K, Saito B, Oguro Y, Sumi H, Yabuki M, Yoshimatsu M, Kosugi Y, Debori Y, Morishita N, Dougan DR, Snell GP, Yoshida S, Ishikawa T Bioorg Med Chem. 2013 Dec 15;21(24):7938-54. doi: 10.1016/j.bmc.2013.09.067. Epub, 2013 Oct 12. PMID:24169315[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Samuel T, Okada K, Hyer M, Welsh K, Zapata JM, Reed JC. cIAP1 Localizes to the nuclear compartment and modulates the cell cycle. Cancer Res. 2005 Jan 1;65(1):210-8. PMID:15665297
- ↑ Xu L, Zhu J, Hu X, Zhu H, Kim HT, LaBaer J, Goldberg A, Yuan J. c-IAP1 cooperates with Myc by acting as a ubiquitin ligase for Mad1. Mol Cell. 2007 Dec 14;28(5):914-22. PMID:18082613 doi:10.1016/j.molcel.2007.10.027
- ↑ Broemer M, Tenev T, Rigbolt KT, Hempel S, Blagoev B, Silke J, Ditzel M, Meier P. Systematic in vivo RNAi analysis identifies IAPs as NEDD8-E3 ligases. Mol Cell. 2010 Dec 10;40(5):810-22. doi: 10.1016/j.molcel.2010.11.011. PMID:21145488 doi:10.1016/j.molcel.2010.11.011
- ↑ Cartier J, Berthelet J, Marivin A, Gemble S, Edmond V, Plenchette S, Lagrange B, Hammann A, Dupoux A, Delva L, Eymin B, Solary E, Dubrez L. Cellular inhibitor of apoptosis protein-1 (cIAP1) can regulate E2F1 transcription factor-mediated control of cyclin transcription. J Biol Chem. 2011 Jul 29;286(30):26406-17. doi: 10.1074/jbc.M110.191239. Epub, 2011 Jun 8. PMID:21653699 doi:10.1074/jbc.M110.191239
- ↑ Bertrand MJ, Lippens S, Staes A, Gilbert B, Roelandt R, De Medts J, Gevaert K, Declercq W, Vandenabeele P. cIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4). PLoS One. 2011;6(9):e22356. doi: 10.1371/journal.pone.0022356. Epub 2011 Sep 12. PMID:21931591 doi:10.1371/journal.pone.0022356
- ↑ Shiokawa Z, Hashimoto K, Saito B, Oguro Y, Sumi H, Yabuki M, Yoshimatsu M, Kosugi Y, Debori Y, Morishita N, Dougan DR, Snell GP, Yoshida S, Ishikawa T. Design, synthesis, and biological activities of novel hexahydropyrazino[1,2-a]indole derivatives as potent inhibitors of apoptosis (IAP) proteins antagonists with improved membrane permeability across MDR1 expressing cells. Bioorg Med Chem. 2013 Dec 15;21(24):7938-54. doi: 10.1016/j.bmc.2013.09.067. Epub, 2013 Oct 12. PMID:24169315 doi:http://dx.doi.org/10.1016/j.bmc.2013.09.067
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