4kjv - Revision history

OCA at 16:00, 20 September 2023

2023-09-20T16:00:17Z

←Older revision		Revision as of 16:00, 20 September 2023
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4kjv]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4KJV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4KJV FirstGlance]. <br>		<table><tr><td colspan='2'>[[4kjv]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4KJV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4KJV FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1RK:6-METHOXY-5-({(3S)-3-[(N-METHYL-L-ALANYL)AMINO]-4-OXO-2,3,3,4,5,6-HEXAHYDRO-5H-SPIRO[1,5-BENZOXAZEPINE-2,4-PYRAN]-5-YL}METHYL)NAPHTHALENE-2-CARBOXYLIC+ACID'>1RK</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 1.7Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1RK:6-METHOXY-5-({(3S)-3-[(N-METHYL-L-ALANYL)AMINO]-4-OXO-2,3,3,4,5,6-HEXAHYDRO-5H-SPIRO[1,5-BENZOXAZEPINE-2,4-PYRAN]-5-YL}METHYL)NAPHTHALENE-2-CARBOXYLIC+ACID'>1RK</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'>[https://proteopedia.org/fgij/fg.htm?mol=4kjv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4kjv OCA], [https://pdbe.org/4kjv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4kjv RCSB], [https://www.ebi.ac.uk/pdbsum/4kjv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4kjv ProSAT]</span></td></tr>		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4kjv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4kjv OCA], [https://pdbe.org/4kjv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4kjv RCSB], [https://www.ebi.ac.uk/pdbsum/4kjv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4kjv ProSAT]</span></td></tr>
	</table>		</table>

OCA at 08:55, 7 December 2022

2022-12-07T08:55:27Z

←Older revision		Revision as of 08:55, 7 December 2022
Line 1:		Line 1:

	==Crystal structure of XIAP-Bir2 with a bound spirocyclic benzoxazepinone inhibitor.==		==Crystal structure of XIAP-Bir2 with a bound spirocyclic benzoxazepinone inhibitor.==
-	<StructureSection load='4kjv' size='340' side='right' caption='[[4kjv]], [[Resolution\|resolution]] 1.70Å' scene=''>	+	<StructureSection load='4kjv' size='340' side='right'caption='[[4kjv]], [[Resolution\|resolution]] 1.70Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4kjv]] 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=4KJV OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4KJV FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4kjv]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4KJV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4KJV FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1RK:6-METHOXY-5-({(3S)-3-[(N-METHYL-L-ALANYL)AMINO]-4-OXO-2,3,3,4,5,6-HEXAHYDRO-5H-SPIRO[1,5-BENZOXAZEPINE-2,4-PYRAN]-5-YL}METHYL)NAPHTHALENE-2-CARBOXYLIC+ACID'>1RK</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=1RK:6-METHOXY-5-({(3S)-3-[(N-METHYL-L-ALANYL)AMINO]-4-OXO-2,3,3,4,5,6-HEXAHYDRO-5H-SPIRO[1,5-BENZOXAZEPINE-2,4-PYRAN]-5-YL}METHYL)NAPHTHALENE-2-CARBOXYLIC+ACID'>1RK</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">[[4j3y\|4j3y]], [[4j44\|4j44]], [[4j45\|4j45]], [[4j46\|4j46]], [[4j47\|4j47]], [[4j48\|4j48]]</td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4kjv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4kjv OCA], [https://pdbe.org/4kjv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4kjv RCSB], [https://www.ebi.ac.uk/pdbsum/4kjv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4kjv ProSAT]</span></td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">XIAP, API3, BIRC4, IAP3 ([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=4kjv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4kjv OCA], [~~http~~://pdbe.org/4kjv PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4kjv RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4kjv PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4kjv ProSAT]</span></td></tr>	+
	</table>		</table>
	== Disease ==		== Disease ==
-	[~~[http~~://www.uniprot.org/uniprot/XIAP_HUMAN XIAP_HUMAN]] Defects in XIAP are the cause of lymphoproliferative syndrome X-linked type 2 (XLP2) [MIM:[~~http~~://omim.org/entry/300635 300635]]. XLP is a rare immunodeficiency characterized by extreme susceptibility to infection with Epstein-Barr virus (EBV). Symptoms include severe or fatal mononucleosis, acquired hypogammaglobulinemia, pancytopenia and malignant lymphoma.<ref>PMID:17080092</ref>	+	[https://www.uniprot.org/uniprot/XIAP_HUMAN XIAP_HUMAN] Defects in XIAP are the cause of lymphoproliferative syndrome X-linked type 2 (XLP2) [MIM:[https://omim.org/entry/300635 300635]. XLP is a rare immunodeficiency characterized by extreme susceptibility to infection with Epstein-Barr virus (EBV). Symptoms include severe or fatal mononucleosis, acquired hypogammaglobulinemia, pancytopenia and malignant lymphoma.<ref>PMID:17080092</ref>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/XIAP_HUMAN XIAP_HUMAN]] Multi-functional protein which regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, copper homeostasis, mitogenic kinase signaling, cell proliferation, as well as cell invasion and metastasis. Acts as a direct caspase inhibitor. Directly bind to the active site pocket of CASP3 and CASP7 and obstructs substrate entry. Inactivates CASP9 by keeping it in a monomeric, inactive state. Acts as an E3 ubiquitin-protein ligase regulating NF-kappa-B signaling and the target proteins for its E3 ubiquitin-protein ligase activity include: RIPK1, CASP3, CASP7, CASP8, CASP9, MAP3K2/MEKK2, DIABLO/SMAC, AIFM1, CCS and BIRC5/survivin. Ubiquitinion of CCS leads to enhancement of its chaperone activity toward its physiologic target, SOD1, rather than proteasomal degradation. Ubiquitinion of MAP3K2/MEKK2 and AIFM1 does not lead to proteasomal degradation. Plays a role in copper homeostasis by ubiquitinationg COMMD1 and promoting its proteasomal degradation. Can also function as E3 ubiquitin-protein ligase of the NEDD8 conjugation pathway, targeting effector caspases for neddylation and inactivation. Regulates the BMP signaling pathway and the SMAD and MAP3K7/TAK1 dependent pathways leading to NF-kappa-B and JNK activation. Acts as an important regulator of innate immune signaling via regulation of Nodlike receptors (NLRs). 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. Acts as a positive regulator of Wnt signaling and ubiquitinates TLE1, TLE2, TLE3, TLE4 and AES. Ubiquitination of TLE3 results in inhibition of its interaction with TCF7L2/TCF4 thereby allowing efficient recruitment and binding of the transcriptional coactivator beta-catenin to TCF7L2/TCF4 that is required to initiate a Wnt-specific transcriptional program.<ref>PMID:9230442</ref> <ref>PMID:11447297</ref> <ref>PMID:12121969</ref> <ref>PMID:14685266</ref> <ref>PMID:14645242</ref> <ref>PMID:17967870</ref> <ref>PMID:19473982</ref> <ref>PMID:21145488</ref> <ref>PMID:20154138</ref> <ref>PMID:22103349</ref> <ref>PMID:22304967</ref> <ref>PMID:17560374</ref>	+	[https://www.uniprot.org/uniprot/XIAP_HUMAN XIAP_HUMAN] Multi-functional protein which regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, copper homeostasis, mitogenic kinase signaling, cell proliferation, as well as cell invasion and metastasis. Acts as a direct caspase inhibitor. Directly bind to the active site pocket of CASP3 and CASP7 and obstructs substrate entry. Inactivates CASP9 by keeping it in a monomeric, inactive state. Acts as an E3 ubiquitin-protein ligase regulating NF-kappa-B signaling and the target proteins for its E3 ubiquitin-protein ligase activity include: RIPK1, CASP3, CASP7, CASP8, CASP9, MAP3K2/MEKK2, DIABLO/SMAC, AIFM1, CCS and BIRC5/survivin. Ubiquitinion of CCS leads to enhancement of its chaperone activity toward its physiologic target, SOD1, rather than proteasomal degradation. Ubiquitinion of MAP3K2/MEKK2 and AIFM1 does not lead to proteasomal degradation. Plays a role in copper homeostasis by ubiquitinationg COMMD1 and promoting its proteasomal degradation. Can also function as E3 ubiquitin-protein ligase of the NEDD8 conjugation pathway, targeting effector caspases for neddylation and inactivation. Regulates the BMP signaling pathway and the SMAD and MAP3K7/TAK1 dependent pathways leading to NF-kappa-B and JNK activation. Acts as an important regulator of innate immune signaling via regulation of Nodlike receptors (NLRs). 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. Acts as a positive regulator of Wnt signaling and ubiquitinates TLE1, TLE2, TLE3, TLE4 and AES. Ubiquitination of TLE3 results in inhibition of its interaction with TCF7L2/TCF4 thereby allowing efficient recruitment and binding of the transcriptional coactivator beta-catenin to TCF7L2/TCF4 that is required to initiate a Wnt-specific transcriptional program.<ref>PMID:9230442</ref> <ref>PMID:11447297</ref> <ref>PMID:12121969</ref> <ref>PMID:14685266</ref> <ref>PMID:14645242</ref> <ref>PMID:17967870</ref> <ref>PMID:19473982</ref> <ref>PMID:21145488</ref> <ref>PMID:20154138</ref> <ref>PMID:22103349</ref> <ref>PMID:22304967</ref> <ref>PMID:17560374</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 22:		Line 20:
	</div>		</div>
	<div class="pdbe-citations 4kjv" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 4kjv" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Ubiquitin protein ligase 3D structures\|Ubiquitin protein ligase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
-	[[Category: ~~Janson, C A~~]]	+	[[Category: Large Structures]]
-	[[Category: ~~Lukacs, C M~~]]	+	[[Category: Janson CA]]
-	[[Category: ~~Apoptosis-apoptosis inhibitor complex]]~~	+	[[Category: Lukacs CM]]
-	~~[[Category: Benzoxazepinone]]~~	+
-	~~[[Category: Bir2]]~~	+
-	~~[[Category: Oncology]]~~	+
-	~~[[Category: Xiap inhibitor~~]]	+

OCA at 09:22, 15 November 2017

2017-11-15T09:22:14Z

←Older revision		Revision as of 09:22, 15 November 2017
Line 22:		Line 22:
	</div>		</div>
	<div class="pdbe-citations 4kjv" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 4kjv" style="background-color:#fffaf0;"></div>
-
-	==See Also==
-	*[[Ubiquitin protein ligase\|Ubiquitin protein ligase]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 17:34, 11 August 2016

2016-08-11T17:34:41Z

←Older revision		Revision as of 17:34, 11 August 2016
Line 1:		Line 1:
		+
	==Crystal structure of XIAP-Bir2 with a bound spirocyclic benzoxazepinone inhibitor.==		==Crystal structure of XIAP-Bir2 with a bound spirocyclic benzoxazepinone inhibitor.==
	<StructureSection load='4kjv' size='340' side='right' caption='[[4kjv]], [[Resolution\|resolution]] 1.70Å' scene=''>		<StructureSection load='4kjv' size='340' side='right' caption='[[4kjv]], [[Resolution\|resolution]] 1.70Å' scene=''>
Line 6:		Line 7:
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4j3y\|4j3y]], [[4j44\|4j44]], [[4j45\|4j45]], [[4j46\|4j46]], [[4j47\|4j47]], [[4j48\|4j48]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4j3y\|4j3y]], [[4j44\|4j44]], [[4j45\|4j45]], [[4j46\|4j46]], [[4j47\|4j47]], [[4j48\|4j48]]</td></tr>
	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">XIAP, API3, BIRC4, IAP3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>		<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">XIAP, API3, BIRC4, IAP3 ([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=4kjv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4kjv OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4kjv RCSB], [http://www.ebi.ac.uk/pdbsum/4kjv PDBsum]</span></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=4kjv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4kjv OCA], [http://pdbe.org/4kjv PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4kjv RCSB], [http://www.ebi.ac.uk/pdbsum/4kjv PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4kjv ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 20:		Line 21:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
		+	<div class="pdbe-citations 4kjv" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==

OCA at 14:30, 4 January 2015

2015-01-04T14:30:13Z

←Older revision		Revision as of 14:30, 4 January 2015
Line 1:		Line 1:
-	~~{{STRUCTURE_4kjv\| PDB=4kjv \| SCENE= }}~~	+	==Crystal structure of XIAP-Bir2 with a bound spirocyclic benzoxazepinone inhibitor.==
-	===Crystal structure of XIAP-Bir2 with a bound spirocyclic benzoxazepinone inhibitor.===	+	<StructureSection load='4kjv' size='340' side='right' caption='[[4kjv]], [[Resolution\|resolution]] 1.70Å' scene=''>
-	{~~{ABSTRACT_PUBMED_24093940}~~}	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>[[4kjv]] 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=4KJV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4KJV FirstGlance]. <br>
-	==Disease==	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1RK:6-METHOXY-5-({(3S)-3-[(N-METHYL-L-ALANYL)AMINO]-4-OXO-2,3,3,4,5,6-HEXAHYDRO-5H-SPIRO[1,5-BENZOXAZEPINE-2,4-PYRAN]-5-YL}METHYL)NAPHTHALENE-2-CARBOXYLIC+ACID'>1RK</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">[[4j3y\|4j3y]], [[4j44\|4j44]], [[4j45\|4j45]], [[4j46\|4j46]], [[4j47\|4j47]], [[4j48\|4j48]]</td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">XIAP, API3, BIRC4, IAP3 ([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=4kjv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4kjv OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4kjv RCSB], [http://www.ebi.ac.uk/pdbsum/4kjv PDBsum]</span></td></tr>
		+	</table>
		+	== Disease ==
	[[http://www.uniprot.org/uniprot/XIAP_HUMAN XIAP_HUMAN]] Defects in XIAP are the cause of lymphoproliferative syndrome X-linked type 2 (XLP2) [MIM:[http://omim.org/entry/300635 300635]]. XLP is a rare immunodeficiency characterized by extreme susceptibility to infection with Epstein-Barr virus (EBV). Symptoms include severe or fatal mononucleosis, acquired hypogammaglobulinemia, pancytopenia and malignant lymphoma.<ref>PMID:17080092</ref>		[[http://www.uniprot.org/uniprot/XIAP_HUMAN XIAP_HUMAN]] Defects in XIAP are the cause of lymphoproliferative syndrome X-linked type 2 (XLP2) [MIM:[http://omim.org/entry/300635 300635]]. XLP is a rare immunodeficiency characterized by extreme susceptibility to infection with Epstein-Barr virus (EBV). Symptoms include severe or fatal mononucleosis, acquired hypogammaglobulinemia, pancytopenia and malignant lymphoma.<ref>PMID:17080092</ref>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/XIAP_HUMAN XIAP_HUMAN]] Multi-functional protein which regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, copper homeostasis, mitogenic kinase signaling, cell proliferation, as well as cell invasion and metastasis. Acts as a direct caspase inhibitor. Directly bind to the active site pocket of CASP3 and CASP7 and obstructs substrate entry. Inactivates CASP9 by keeping it in a monomeric, inactive state. Acts as an E3 ubiquitin-protein ligase regulating NF-kappa-B signaling and the target proteins for its E3 ubiquitin-protein ligase activity include: RIPK1, CASP3, CASP7, CASP8, CASP9, MAP3K2/MEKK2, DIABLO/SMAC, AIFM1, CCS and BIRC5/survivin. Ubiquitinion of CCS leads to enhancement of its chaperone activity toward its physiologic target, SOD1, rather than proteasomal degradation. Ubiquitinion of MAP3K2/MEKK2 and AIFM1 does not lead to proteasomal degradation. Plays a role in copper homeostasis by ubiquitinationg COMMD1 and promoting its proteasomal degradation. Can also function as E3 ubiquitin-protein ligase of the NEDD8 conjugation pathway, targeting effector caspases for neddylation and inactivation. Regulates the BMP signaling pathway and the SMAD and MAP3K7/TAK1 dependent pathways leading to NF-kappa-B and JNK activation. Acts as an important regulator of innate immune signaling via regulation of Nodlike receptors (NLRs). 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. Acts as a positive regulator of Wnt signaling and ubiquitinates TLE1, TLE2, TLE3, TLE4 and AES. Ubiquitination of TLE3 results in inhibition of its interaction with TCF7L2/TCF4 thereby allowing efficient recruitment and binding of the transcriptional coactivator beta-catenin to TCF7L2/TCF4 that is required to initiate a Wnt-specific transcriptional program.<ref>PMID:9230442</ref> <ref>PMID:11447297</ref> <ref>PMID:12121969</ref> <ref>PMID:14685266</ref> <ref>PMID:14645242</ref> <ref>PMID:17967870</ref> <ref>PMID:19473982</ref> <ref>PMID:21145488</ref> <ref>PMID:20154138</ref> <ref>PMID:22103349</ref> <ref>PMID:22304967</ref> <ref>PMID:17560374</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The IAPs are key regulators of the apoptotic pathways and are commonly overexpressed in many cancer cells. IAPs contain one to three BIR domains that are crucial for their inhibitory function. The pro-survival properties of XIAP come from binding of the BIR domains to the pro-apoptotic caspases. The BIR3 domain of XIAP binds and inhibits caspase 9, while the BIR2 domain binds and inhibits the terminal caspases 3 and 7. While XIAP BIR3 inhibitors have previously been reported, they also inhibit cIAP1/2 and promote the release of TNFalpha, potentially limiting their therapeutic utility. This paper will focus on the optimization of selective XIAP BIR2 inhibitors leading to the discovery of highly potent benzodiazepinone 36 (IC50 = 45 nM), which has high levels of selectivity over XIAP BIR3 and cIAP1 BIR2/3 and shows efficacy in a xenograft pharmacodynamic model monitoring caspase activity while not promoting the release of TNFalpha in vitro.

-	~~==Function==~~	+	Optimization of Benzodiazepinones as Selective Inhibitors of the X-Linked Inhibitor of Apoptosis Protein (XIAP) Second Baculovirus IAP Repeat (BIR2) Domain.,Kester RF, Donnell AF, Lou Y, Remiszewski SW, Lombardo LJ, Chen S, Le NT, Lo J, Moliterni JA, Han X, Hogg JH, Liang W, Michoud C, Rupert KC, Mischke S, Le K, Weisel M, Janson CA, Lukacs CM, Fretland AJ, Hong K, Polonskaia A, Gao L, Li S, Solis DS, Aguilar D, Tardell C, Dvorozniak M, Tannu S, Lee EC, Schutt AD, Goggin B J Med Chem. 2013 Oct 7. PMID:24093940<ref>PMID:24093940</ref>
-	~~[[http://www~~.~~uniprot.org/uniprot/XIAP_HUMAN XIAP_HUMAN]] Multi-functional protein which regulates not only caspases and apoptosis~~, ~~but also modulates inflammatory signaling and immunity~~, ~~copper homeostasis~~, ~~mitogenic kinase signaling~~, ~~cell proliferation~~, as well as cell invasion and metastasis. Acts as a direct caspase inhibitor. Directly bind to the active site pocket of CASP3 and CASP7 and obstructs substrate entry. Inactivates CASP9 by keeping it in a monomeric, ~~inactive state. Acts as an E3 ubiquitin-protein ligase regulating NF-kappa-B signaling and the target proteins for its E3 ubiquitin-protein ligase activity include: RIPK1~~, ~~CASP3~~, ~~CASP7~~, ~~CASP8~~, ~~CASP9~~, ~~MAP3K2/MEKK2~~, ~~DIABLO/SMAC~~, ~~AIFM1~~, ~~CCS and BIRC5/survivin. Ubiquitinion of CCS leads to enhancement of its chaperone activity toward its physiologic target~~, ~~SOD1~~, rather than proteasomal degradation. Ubiquitinion of MAP3K2/MEKK2 and AIFM1 does not lead to proteasomal degradation. Plays a role in copper homeostasis by ubiquitinationg COMMD1 and promoting its proteasomal degradation. Can also function as E3 ubiquitin-protein ligase of the NEDD8 conjugation pathway, targeting effector caspases for neddylation and inactivation. Regulates the BMP signaling pathway and the SMAD and MAP3K7/TAK1 dependent pathways leading to NF-kappa-B and JNK activation. Acts as an important regulator of innate immune signaling via regulation of Nodlike receptors (NLRs). 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. Acts as a positive regulator of Wnt signaling and ubiquitinates TLE1, ~~TLE2~~, ~~TLE3~~, ~~TLE4 and AES~~. Ubiquitination of TLE3 results in inhibition of its interaction with TCF7L2/TCF4 thereby allowing efficient recruitment and binding of the transcriptional coactivator beta-catenin to TCF7L2/TCF4 that is required to initiate a Wnt-specific transcriptional program.~~<ref>~~PMID:9230442</ref> <ref>PMID:11447297</ref> <ref>PMID:12121969</ref> <ref>PMID:14685266</ref> <ref>PMID:14645242</ref> <ref>PMID:17967870</ref> <ref>PMID:19473982</ref> <ref>PMID:21145488</ref> <ref>PMID:20154138</ref> <ref>PMID:22103349</ref> <ref>PMID:22304967</ref> <ref>PMID:~~17560374~~</ref>	+

-	~~==About this Structure==~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[4kjv]] 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=4KJV OCA].~~	+	</div>

-	==~~Reference~~==	+	==See Also==
-	~~<ref group~~=~~"xtra">PMID:024093940</ref>~~<references ~~group="xtra"~~/><~~references~~/>	+	*[[Ubiquitin protein ligase\|Ubiquitin protein ligase]]
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
	[[Category: Human]]		[[Category: Human]]
-	[[Category: Janson, C A.]]	+	[[Category: Janson, C A]]
-	[[Category: Lukacs, C M.]]	+	[[Category: Lukacs, C M]]
	[[Category: Apoptosis-apoptosis inhibitor complex]]		[[Category: Apoptosis-apoptosis inhibitor complex]]
	[[Category: Benzoxazepinone]]		[[Category: Benzoxazepinone]]

OCA at 09:20, 5 February 2014

2014-02-05T09:20:30Z

←Older revision		Revision as of 09:20, 5 February 2014
Line 1:		Line 1:
	{{STRUCTURE_4kjv\| PDB=4kjv \| SCENE= }}		{{STRUCTURE_4kjv\| PDB=4kjv \| SCENE= }}
	===Crystal structure of XIAP-Bir2 with a bound spirocyclic benzoxazepinone inhibitor.===		===Crystal structure of XIAP-Bir2 with a bound spirocyclic benzoxazepinone inhibitor.===
-	{{~~ABSTRACT_PUBMED_24083782~~}}	+	{{ABSTRACT_PUBMED_24093940}}

	==Disease==		==Disease==
Line 10:		Line 10:

	==About this Structure==		==About this Structure==
-	[[4kjv]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4KJV OCA].	+	[[4kjv]] 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=4KJV OCA].

	==Reference==		==Reference==
-	<ref group="xtra">PMID:~~024083782~~</ref><references group="xtra"/><references/>	+	<ref group="xtra">PMID:024093940</ref><references group="xtra"/><references/>
		+	[[Category: Human]]
	[[Category: Janson, C A.]]		[[Category: Janson, C A.]]
	[[Category: Lukacs, C M.]]		[[Category: Lukacs, C M.]]

OCA at 10:24, 27 November 2013

2013-11-27T10:24:30Z

←Older revision		Revision as of 10:24, 27 November 2013
Line 1:		Line 1:
-	~~'''Unreleased~~ structure~~'''~~	+	{{STRUCTURE_4kjv\| PDB=4kjv \| SCENE= }}
		+	===Crystal structure of XIAP-Bir2 with a bound spirocyclic benzoxazepinone inhibitor.===
		+	{{ABSTRACT_PUBMED_24083782}}

-	~~The~~ entry ~~4kjv~~ is ~~ON HOLD~~ ~~until Paper Publication~~	+	==Disease==
		+	[[http://www.uniprot.org/uniprot/XIAP_HUMAN XIAP_HUMAN]] Defects in XIAP are the cause of lymphoproliferative syndrome X-linked type 2 (XLP2) [MIM:[http://omim.org/entry/300635 300635]]. XLP is a rare immunodeficiency characterized by extreme susceptibility to infection with Epstein-Barr virus (EBV). Symptoms include severe or fatal mononucleosis, acquired hypogammaglobulinemia, pancytopenia and malignant lymphoma.<ref>PMID:17080092</ref>

-	~~Authors~~: ~~Lukacs~~, C.M., ~~Janson~~, C.A.	+	==Function==
		+	[[http://www.uniprot.org/uniprot/XIAP_HUMAN XIAP_HUMAN]] Multi-functional protein which regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, copper homeostasis, mitogenic kinase signaling, cell proliferation, as well as cell invasion and metastasis. Acts as a direct caspase inhibitor. Directly bind to the active site pocket of CASP3 and CASP7 and obstructs substrate entry. Inactivates CASP9 by keeping it in a monomeric, inactive state. Acts as an E3 ubiquitin-protein ligase regulating NF-kappa-B signaling and the target proteins for its E3 ubiquitin-protein ligase activity include: RIPK1, CASP3, CASP7, CASP8, CASP9, MAP3K2/MEKK2, DIABLO/SMAC, AIFM1, CCS and BIRC5/survivin. Ubiquitinion of CCS leads to enhancement of its chaperone activity toward its physiologic target, SOD1, rather than proteasomal degradation. Ubiquitinion of MAP3K2/MEKK2 and AIFM1 does not lead to proteasomal degradation. Plays a role in copper homeostasis by ubiquitinationg COMMD1 and promoting its proteasomal degradation. Can also function as E3 ubiquitin-protein ligase of the NEDD8 conjugation pathway, targeting effector caspases for neddylation and inactivation. Regulates the BMP signaling pathway and the SMAD and MAP3K7/TAK1 dependent pathways leading to NF-kappa-B and JNK activation. Acts as an important regulator of innate immune signaling via regulation of Nodlike receptors (NLRs). 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. Acts as a positive regulator of Wnt signaling and ubiquitinates TLE1, TLE2, TLE3, TLE4 and AES. Ubiquitination of TLE3 results in inhibition of its interaction with TCF7L2/TCF4 thereby allowing efficient recruitment and binding of the transcriptional coactivator beta-catenin to TCF7L2/TCF4 that is required to initiate a Wnt-specific transcriptional program.<ref>PMID:9230442</ref> <ref>PMID:11447297</ref> <ref>PMID:12121969</ref> <ref>PMID:14685266</ref> <ref>PMID:14645242</ref> <ref>PMID:17967870</ref> <ref>PMID:19473982</ref> <ref>PMID:21145488</ref> <ref>PMID:20154138</ref> <ref>PMID:22103349</ref> <ref>PMID:22304967</ref> <ref>PMID:17560374</ref>

-	~~Description: Crystal~~ structure ~~of XIAP~~-Bir2 ~~with a bound spirocyclic benzoxazepinone~~ inhibitor.	+	==About this Structure==
		+	[[4kjv]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4KJV OCA].
		+
		+	==Reference==
		+	<ref group="xtra">PMID:024083782</ref><references group="xtra"/><references/>
		+	[[Category: Janson, C A.]]
		+	[[Category: Lukacs, C M.]]
		+	[[Category: Apoptosis-apoptosis inhibitor complex]]
		+	[[Category: Benzoxazepinone]]
		+	[[Category: Bir2]]
		+	[[Category: Oncology]]
		+	[[Category: Xiap inhibitor]]

OCA: Protected "4kjv" [edit=sysop:move=sysop]

2013-05-16T06:57:15Z

Protected "4kjv" [edit=sysop:move=sysop]

←Older revision

Revision as of 06:57, 16 May 2013

OCA: New page: '''Unreleased structure''' The entry 4kjv is ON HOLD until Paper Publication Authors: Lukacs, C.M., Janson, C.A. Description: Crystal structure of XIAP-Bir2 with a bound spirocyclic be...

2013-05-16T06:57:13Z

New page: '''Unreleased structure''' The entry 4kjv is ON HOLD until Paper Publication Authors: Lukacs, C.M., Janson, C.A. Description: Crystal structure of XIAP-Bir2 with a bound spirocyclic be...

New page

'''Unreleased structure'''

The entry 4kjv is ON HOLD until Paper Publication

Authors: Lukacs, C.M., Janson, C.A.

Description: Crystal structure of XIAP-Bir2 with a bound spirocyclic benzoxazepinone inhibitor.