4lge

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{{STRUCTURE_4lge| PDB=4lge | SCENE= }}
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==Crystal structure of clAP1 BIR3 bound to T3261256==
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===Crystal structure of clAP1 BIR3 bound to T3261256===
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<StructureSection load='4lge' size='340' side='right' caption='[[4lge]], [[Resolution|resolution]] 1.55&Aring;' scene=''>
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{{ABSTRACT_PUBMED_23928071}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4lge]] 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=4LGE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4LGE FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1Y0:(4S,6AR,7AS)-5-{(2S)-2-CYCLOHEXYL-2-[(N-METHYL-L-ALANYL)AMINO]ACETYL}-N-[(4R)-3,4-DIHYDRO-2H-CHROMEN-4-YL]OCTAHYDRO-1H-CYCLOPROPA[4,5]PYRROLO[1,2-A]PYRAZINE-4-CARBOXAMIDE'>1Y0</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4lgu|4lgu]]</td></tr>
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<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>
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<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=4lge FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lge OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4lge RCSB], [http://www.ebi.ac.uk/pdbsum/4lge PDBsum]</span></td></tr>
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</table>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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We recently reported the discovery of octahydropyrrolo[1,2-a]pyrazine A as a lead compound for an inhibitor of apoptosis proteins (IAP) antagonist. To develop IAP antagonists with favorable PK profiles, we designed novel tri-cyclic compounds, octahydro-1H-cyclopropa[4,5]pyrrolo[1,2-a]pyrazines 1 and 2 based on co-crystal structural analysis of A with cellular IAP-1 (cIAP-1). The additional cyclopropane moiety was used to block the predicted metabolic site of compound A without detriment to the binding affinity for cIAP. Compounds 1 and 2 were stereoselectively synthesized via intermediates 4a and 5b', which were obtained by Simmons-Smith cyclopropanation of ethylester 3a and silyl ether 3b'. Compounds 1 and 2 showed strong growth inhibition in MDA-MB-231 breast cancer cells and improved metabolic stability in comparison to A. Compound 2 exhibited significant in vivo PD effects to increase tumor necrosis factor-alpha mRNA in a dose dependent manner.
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==Function==
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Design, stereoselective synthesis, and biological evaluation of novel tri-cyclic compounds as inhibitor of apoptosis proteins (IAP) antagonists.,Asano M, Hashimoto K, Saito B, Shiokawa Z, Sumi H, Yabuki M, Yoshimatsu M, Aoyama K, Hamada T, Morishita N, Dougan DR, Mol CD, Yoshida S, Ishikawa T Bioorg Med Chem. 2013 Sep 15;21(18):5725-37. doi: 10.1016/j.bmc.2013.07.020. Epub, 2013 Jul 18. PMID:23928071<ref>PMID:23928071</ref>
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[[http://www.uniprot.org/uniprot/BIRC2_HUMAN 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.<ref>PMID:15665297</ref> <ref>PMID:18082613</ref> <ref>PMID:21145488</ref> <ref>PMID:21653699</ref> <ref>PMID:21931591</ref>
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[4lge]] 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=4LGE OCA].
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</div>
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:023928071</ref><references group="xtra"/><references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Dougan, D R.]]
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[[Category: Dougan, D R]]
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[[Category: 1 card domain]]
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[[Category: Card domain]]
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[[Category: 1 ring-type zinc finger]]
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[[Category: Ring-type zinc finger]]
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[[Category: 3 bir repeat]]
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[[Category: Bir repeat]]
[[Category: Lap family]]
[[Category: Lap family]]
[[Category: Ligase-ligase inhibitor complex]]
[[Category: Ligase-ligase inhibitor complex]]

Revision as of 15:15, 21 December 2014

Crystal structure of clAP1 BIR3 bound to T3261256

4lge, resolution 1.55Å

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