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4hy5

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Revision as of 04:58, 9 September 2015

Crystal structure of cIAP1 BIR3 bound to T3256336

Structural highlights

4hy5 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:	4hy4, 4hy0
Gene:	API1, BIRC2, IAP2, MIHB, RNF48 (HUMAN)
Resources:	FirstGlance, OCA, RCSB, PDBsum

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

To develop novel inhibitor of apoptosis (IAP) proteins antagonists, we designed a bicyclic octahydropyrrolo[1,2-a]pyrazine scaffold as a novel proline bioisostere. This design was based on the X-ray co-crystal structure of four N-terminal amino acid residues (AVPI) of the second mitochondria-derived activator of caspase (Smac) with the X-chromosome-linked IAP (XIAP) protein. Lead optimization of this scaffold to improve oral absorption yielded compound 45, which showed potent cellular IAP1 (cIAP1 IC50: 1.3 nM) and XIAP (IC50: 200 nM) inhibitory activity, in addition to potent tumor growth inhibitory activity (GI50: 1.8 nM) in MDA-MB-231 breast cancer cells. X-ray crystallographic analysis of compound 45 bound to XIAP and to cIAP1 was achieved, revealing the various key interactions that contribute to the higher cIAPI affinity of compound 45 over XIAP. Due to its potent IAP inhibitory activities, compound 45 (T-3256336) caused tumor regression in a MDA-MB-231 tumor xenograft model (T/C: -53% at 30 mg/kg).

Design and Synthesis of Potent Inhibitor of Apoptosis (IAP) Proteins Antagonists Bearing an Octahydropyrrolo[1,2-a]pyrazine Scaffold as a Novel Proline Mimetic.,Hashimoto K, Saito B, Miyamoto N, Oguro Y, Tomita D, Shiokawa Z, Asano M, Kakei H, Taya N, Kawasaki M, Sumi H, Yabuki M, Iwai K, Yoshida S, Yoshimatsu M, Aoyama K, Kosugi Y, Kojima T, Morishita N, Dougan DR, Snell GP, Imamura S, Ishikawa T J Med Chem. 2013 Jan 8. PMID:23298277^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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
↑ Hashimoto K, Saito B, Miyamoto N, Oguro Y, Tomita D, Shiokawa Z, Asano M, Kakei H, Taya N, Kawasaki M, Sumi H, Yabuki M, Iwai K, Yoshida S, Yoshimatsu M, Aoyama K, Kosugi Y, Kojima T, Morishita N, Dougan DR, Snell GP, Imamura S, Ishikawa T. Design and Synthesis of Potent Inhibitor of Apoptosis (IAP) Proteins Antagonists Bearing an Octahydropyrrolo[1,2-a]pyrazine Scaffold as a Novel Proline Mimetic. J Med Chem. 2013 Jan 8. PMID:23298277 doi:10.1021/jm301674z

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4hy5"

@@ Line 2: / Line 2: @@
 <StructureSection load='4hy5' size='340' side='right' caption='[[4hy5]], [[Resolution|resolution]] 1.75&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4hy5]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4HY5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4HY5 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4hy5]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4HY5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4HY5 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1AQ:(3S,7R,8AR)-2-{(2S)-2-(4,4-DIFLUOROCYCLOHEXYL)-2-[(N-METHYL-L-ALANYL)AMINO]ACETYL}-N-[(4R)-3,4-DIHYDRO-2H-CHROMEN-4-YL]-7-ETHOXYOCTAHYDROPYRROLO[1,2-A]PYRAZINE-3-CARBOXAMIDE'>1AQ</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4hy4|4hy4]], [[4hy0|4hy0]]</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">API1, BIRC2, IAP2, MIHB, RNF48 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">API1, BIRC2, IAP2, MIHB, RNF48 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4hy5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hy5 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4hy5 RCSB], [http://www.ebi.ac.uk/pdbsum/4hy5 PDBsum]</span></td></tr>
 </table>
@@ Line 18: / Line 18: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+==See Also==
+*[[Baculoviral IAP repeat-containing protein|Baculoviral IAP repeat-containing protein]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
+[[Category: Human]]
-[[Category: D R., Dougan]]
+[[Category: Dougan, D R]]
-[[Category: G P., Snell]]
+[[Category: Snell, G P]]
 [[Category: Bir repeat]]
 [[Category: Card domain]]

4hy5

From Proteopedia

Revision as of 04:58, 9 September 2015

Crystal structure of cIAP1 BIR3 bound to T3256336

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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