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5m6n

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Revision as of 11:02, 12 August 2020

Small Molecule inhibitors of IAP

Structural highlights

5m6n is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
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

XIAP and cIAP1 are members of the inhibitor of apoptosis protein (IAP) family and are key regulators of anti-apoptotic and pro-survival signaling pathways. Overexpression of IAPs occurs in various cancers and has been associated with tumor progression and resistance to treatment. Structure-based drug design (SBDD) guided by structural information from X-ray crystallography, computational studies and NMR solution conformational analysis was successfully applied to a fragment-derived lead resulting in AT-IAP, a potent, orally bioavailable, dual antagonist of XIAP and cIAP1 and a structurally novel chemical probe for IAP biology.

Discovery of a Potent Non-peptidomimetic, Small-Molecule Antagonist of Cellular Inhibitor of Apoptosis Protein 1 (cIAP1) and X-linked Inhibitor of Apoptosis Protein (XIAP).,Tamanini E, Buck IM, Chessari G, Chiarparin E, Day JEH, Frederickson M, Griffiths-Jones CM, Hearn K, Heightman TD, Iqbal A, Johnson CN, Lewis EJ, Martins V, Peakman T, Reader M, Rich SJ, Ward GA, Williams PA, Wilsher NE J Med Chem. 2017 May 11. doi: 10.1021/acs.jmedchem.6b01877. PMID:28492317^[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
↑ Tamanini E, Buck IM, Chessari G, Chiarparin E, Day JEH, Frederickson M, Griffiths-Jones CM, Hearn K, Heightman TD, Iqbal A, Johnson CN, Lewis EJ, Martins V, Peakman T, Reader M, Rich SJ, Ward GA, Williams PA, Wilsher NE. Discovery of a Potent Non-peptidomimetic, Small-Molecule Antagonist of Cellular Inhibitor of Apoptosis Protein 1 (cIAP1) and X-linked Inhibitor of Apoptosis Protein (XIAP). J Med Chem. 2017 May 11. doi: 10.1021/acs.jmedchem.6b01877. PMID:28492317 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b01877

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/5m6n"

@@ Line 1: / Line 1: @@
 ==Small Molecule inhibitors of IAP==
-<StructureSection load='5m6n' size='340' side='right' caption='[[5m6n]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
+<StructureSection load='5m6n' size='340' side='right'caption='[[5m6n]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5m6n]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5M6N OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5M6N FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5m6n]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5M6N OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5M6N FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7H9:1-[6-[(4-FLUOROPHENYL)METHYL]-3,3-DIMETHYL-2~{H}-PYRROLO[3,2-B]PYRIDIN-1-YL]-2-[(2~{R},5~{R})-5-METHYL-2-[[(3~{R})-3-METHYLMORPHOLIN-4-YL]METHYL]PIPERAZIN-4-IUM-1-YL]ETHANONE'>7H9</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7H9:1-[6-[(4-FLUOROPHENYL)METHYL]-3,3-DIMETHYL-2~{H}-PYRROLO[3,2-B]PYRIDIN-1-YL]-2-[(2~{R},5~{R})-5-METHYL-2-[[(3~{R})-3-METHYLMORPHOLIN-4-YL]METHYL]PIPERAZIN-4-IUM-1-YL]ETHANONE'>7H9</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=5m6n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5m6n OCA], [http://pdbe.org/5m6n PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5m6n RCSB], [http://www.ebi.ac.uk/pdbsum/5m6n PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5m6n ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5m6n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5m6n OCA], [http://pdbe.org/5m6n PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5m6n RCSB], [http://www.ebi.ac.uk/pdbsum/5m6n PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5m6n ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 18: / Line 18: @@
 </div>
 <div class="pdbe-citations 5m6n" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Baculoviral IAP repeat-containing protein 3D structures|Baculoviral IAP repeat-containing protein 3D structures]]
+*[[Ubiquitin protein ligase 3D structures|Ubiquitin protein ligase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Large Structures]]
 [[Category: Williams, P A]]
 [[Category: Apoptosis]]

5m6n

From Proteopedia

Revision as of 11:02, 12 August 2020

Small Molecule inhibitors of IAP

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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