5aep - Revision history

OCA at 11:08, 10 January 2024

OCA — Wed, 10 Jan 2024 11:08:24 GMT

←Older revision		Revision as of 11:08, 10 January 2024
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[5aep]] is a 1 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=5AEP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5AEP FirstGlance]. <br>		<table><tr><td colspan='2'>[[5aep]] is a 1 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=5AEP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5AEP FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene>, <scene name='pdbligand=QUP:1-(5-CHLORO-2-METHYLPHENYL)-4-(PYRROLO[2,1-F][1,2,4]TRIAZIN-4-YL)-1H-PYRROLE-2-CARBOXAMIDE'>QUP</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]] 1.95Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene>, <scene name='pdbligand=QUP:1-(5-CHLORO-2-METHYLPHENYL)-4-(PYRROLO[2,1-F][1,2,4]TRIAZIN-4-YL)-1H-PYRROLE-2-CARBOXAMIDE'>QUP</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=5aep FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5aep OCA], [https://pdbe.org/5aep PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5aep RCSB], [https://www.ebi.ac.uk/pdbsum/5aep PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5aep 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=5aep FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5aep OCA], [https://pdbe.org/5aep PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5aep RCSB], [https://www.ebi.ac.uk/pdbsum/5aep PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5aep ProSAT]</span></td></tr>
	</table>		</table>

OCA at 04:54, 25 May 2023

OCA — Thu, 25 May 2023 04:54:12 GMT

←Older revision		Revision as of 04:54, 25 May 2023
Line 3:		Line 3:
	<StructureSection load='5aep' size='340' side='right'caption='[[5aep]], [[Resolution\|resolution]] 1.95Å' scene=''>		<StructureSection load='5aep' size='340' side='right'caption='[[5aep]], [[Resolution\|resolution]] 1.95Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5aep]] is a 1 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=5AEP OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5AEP FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5aep]] is a 1 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=5AEP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5AEP FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=QUP:1-(5-CHLORO-2-METHYLPHENYL)-4-(PYRROLO[2,1-F][1,2,4]TRIAZIN-4-YL)-1H-PYRROLE-2-CARBOXAMIDE'>QUP</scene~~></td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene>, <scene name='pdbligand=QUP:1-(5-CHLORO-2-METHYLPHENYL)-4-(PYRROLO[2,1-F][1,2,4]TRIAZIN-4-YL)-1H-PYRROLE-2-CARBOXAMIDE'>QUP</scene></td></tr>
-	~~<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</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=5aep FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5aep OCA], [https://pdbe.org/5aep PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5aep RCSB], [https://www.ebi.ac.uk/pdbsum/5aep PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5aep ProSAT]</span></td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </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=5aep FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5aep OCA], [~~http~~://pdbe.org/5aep PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5aep RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5aep PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5aep ProSAT]</span></td></tr>	+
	</table>		</table>
	== Disease ==		== Disease ==
-	[~~[http~~://www.uniprot.org/uniprot/JAK2_HUMAN JAK2_HUMAN]] Note=Chromosomal aberrations involving JAK2 are found in both chronic and acute forms of eosinophilic, lymphoblastic and myeloid leukemia. Translocation t(8;9)(p22;p24) with PCM1 links the protein kinase domain of JAK2 to the major portion of PCM1. Translocation t(9;12)(p24;p13) with ETV6. Defects in JAK2 are a cause of susceptibility to Budd-Chiari syndrome (BDCHS) [MIM:[~~http~~://omim.org/entry/600880 600880]]. A syndrome caused by obstruction of hepatic venous outflow involving either the hepatic veins or the terminal segment of the inferior vena cava. Obstructions are generally caused by thrombosis and lead to hepatic congestion and ischemic necrosis. Clinical manifestations observed in the majority of patients include hepatomegaly, right upper quadrant pain and abdominal ascites. Budd-Chiari syndrome is associated with a combination of disease states including primary myeloproliferative syndromes and thrombophilia due to factor V Leiden, protein C deficiency and antithrombin III deficiency. Budd-Chiari syndrome is a rare but typical complication in patients with polycythemia vera. Defects in JAK2 are a cause of polycythemia vera (PV) [MIM:[~~http~~://omim.org/entry/263300 263300]]. A myeloproliferative disorder characterized by abnormal proliferation of all hematopoietic bone marrow elements, erythroid hyperplasia, an absolute increase in total blood volume, but also by myeloid leukocytosis, thrombocytosis and splenomegaly.<ref>PMID:15781101</ref> <ref>PMID:15793561</ref> <ref>PMID:15858187</ref> <ref>PMID:16603627</ref> Defects in JAK2 gene may be the cause of thrombocythemia type 3 (THCYT3) [MIM:[~~http~~://omim.org/entry/614521 614521]]. A myeloproliferative disorder characterized by elevated platelet levels due to sustained proliferation of megakaryocytes, and frequently lead to thrombotic and haemorrhagic complications.<ref>PMID:16325696</ref> <ref>PMID:22397670</ref> Defects in JAK2 are a cause of myelofibrosis (MYELOF) [MIM:[~~http~~://omim.org/entry/254450 254450]]. Myelofibrosis is a disorder characterized by replacement of the bone marrow by fibrous tissue, occurring in association with a myeloproliferative disorder. Clinical manifestations may include anemia, pallor, splenomegaly, hypermetabolic state, petechiae, ecchymosis, bleeding, lymphadenopathy, hepatomegaly, portal hypertension. Defects in JAK2 are a cause of acute myelogenous leukemia (AML) [MIM:[~~http~~://omim.org/entry/601626 601626]]. AML is a malignant disease in which hematopoietic precursors are arrested in an early stage of development.<ref>PMID:16247455</ref>	+	[https://www.uniprot.org/uniprot/JAK2_HUMAN JAK2_HUMAN] Note=Chromosomal aberrations involving JAK2 are found in both chronic and acute forms of eosinophilic, lymphoblastic and myeloid leukemia. Translocation t(8;9)(p22;p24) with PCM1 links the protein kinase domain of JAK2 to the major portion of PCM1. Translocation t(9;12)(p24;p13) with ETV6. Defects in JAK2 are a cause of susceptibility to Budd-Chiari syndrome (BDCHS) [MIM:[https://omim.org/entry/600880 600880]. A syndrome caused by obstruction of hepatic venous outflow involving either the hepatic veins or the terminal segment of the inferior vena cava. Obstructions are generally caused by thrombosis and lead to hepatic congestion and ischemic necrosis. Clinical manifestations observed in the majority of patients include hepatomegaly, right upper quadrant pain and abdominal ascites. Budd-Chiari syndrome is associated with a combination of disease states including primary myeloproliferative syndromes and thrombophilia due to factor V Leiden, protein C deficiency and antithrombin III deficiency. Budd-Chiari syndrome is a rare but typical complication in patients with polycythemia vera. Defects in JAK2 are a cause of polycythemia vera (PV) [MIM:[https://omim.org/entry/263300 263300]. A myeloproliferative disorder characterized by abnormal proliferation of all hematopoietic bone marrow elements, erythroid hyperplasia, an absolute increase in total blood volume, but also by myeloid leukocytosis, thrombocytosis and splenomegaly.<ref>PMID:15781101</ref> <ref>PMID:15793561</ref> <ref>PMID:15858187</ref> <ref>PMID:16603627</ref> Defects in JAK2 gene may be the cause of thrombocythemia type 3 (THCYT3) [MIM:[https://omim.org/entry/614521 614521]. A myeloproliferative disorder characterized by elevated platelet levels due to sustained proliferation of megakaryocytes, and frequently lead to thrombotic and haemorrhagic complications.<ref>PMID:16325696</ref> <ref>PMID:22397670</ref> Defects in JAK2 are a cause of myelofibrosis (MYELOF) [MIM:[https://omim.org/entry/254450 254450]. Myelofibrosis is a disorder characterized by replacement of the bone marrow by fibrous tissue, occurring in association with a myeloproliferative disorder. Clinical manifestations may include anemia, pallor, splenomegaly, hypermetabolic state, petechiae, ecchymosis, bleeding, lymphadenopathy, hepatomegaly, portal hypertension. Defects in JAK2 are a cause of acute myelogenous leukemia (AML) [MIM:[https://omim.org/entry/601626 601626]. AML is a malignant disease in which hematopoietic precursors are arrested in an early stage of development.<ref>PMID:16247455</ref>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/JAK2_HUMAN JAK2_HUMAN]] Non-receptor tyrosine kinase involved in various processes such as cell growth, development, differentiation or histone modifications. Mediates essential signaling events in both innate and adaptive immunity. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors such as growth hormone (GHR), prolactin (PRLR), leptin (LEPR), erythropoietin (EPOR), thrombopoietin (THPO); or type II receptors including IFN-alpha, IFN-beta, IFN-gamma and multiple interleukins. Following ligand-binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins. Subsequently, phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then form homodimer or heterodimers and translocate to the nucleus to activate gene transcription. For example, cell stimulation with erythropoietin (EPO) during erythropoiesis leads to JAK2 autophosphorylation, activation, and its association with erythropoietin receptor (EPOR) that becomes phosphorylated in its cytoplasmic domain. Then, STAT5 (STAT5A or STAT5B) is recruited, phosphorylated and activated by JAK2. Once activated, dimerized STAT5 translocates into the nucleus and promotes the transcription of several essential genes involved in the modulation of erythropoiesis. In addition, JAK2 mediates angiotensin-2-induced ARHGEF1 phosphorylation. Plays a role in cell cycle by phosphorylating CDKN1B. Cooperates with TEC through reciprocal phosphorylation to mediate cytokine-driven activation of FOS transcription. In the nucleus, plays a key role in chromatin by specifically mediating phosphorylation of 'Tyr-41' of histone H3 (H3Y41ph), a specific tag that promotes exclusion of CBX5 (HP1 alpha) from chromatin.<ref>PMID:12023369</ref> <ref>PMID:19783980</ref> <ref>PMID:20098430</ref> <ref>PMID:21423214</ref>	+	[https://www.uniprot.org/uniprot/JAK2_HUMAN JAK2_HUMAN] Non-receptor tyrosine kinase involved in various processes such as cell growth, development, differentiation or histone modifications. Mediates essential signaling events in both innate and adaptive immunity. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors such as growth hormone (GHR), prolactin (PRLR), leptin (LEPR), erythropoietin (EPOR), thrombopoietin (THPO); or type II receptors including IFN-alpha, IFN-beta, IFN-gamma and multiple interleukins. Following ligand-binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins. Subsequently, phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then form homodimer or heterodimers and translocate to the nucleus to activate gene transcription. For example, cell stimulation with erythropoietin (EPO) during erythropoiesis leads to JAK2 autophosphorylation, activation, and its association with erythropoietin receptor (EPOR) that becomes phosphorylated in its cytoplasmic domain. Then, STAT5 (STAT5A or STAT5B) is recruited, phosphorylated and activated by JAK2. Once activated, dimerized STAT5 translocates into the nucleus and promotes the transcription of several essential genes involved in the modulation of erythropoiesis. In addition, JAK2 mediates angiotensin-2-induced ARHGEF1 phosphorylation. Plays a role in cell cycle by phosphorylating CDKN1B. Cooperates with TEC through reciprocal phosphorylation to mediate cytokine-driven activation of FOS transcription. In the nucleus, plays a key role in chromatin by specifically mediating phosphorylation of 'Tyr-41' of histone H3 (H3Y41ph), a specific tag that promotes exclusion of CBX5 (HP1 alpha) from chromatin.<ref>PMID:12023369</ref> <ref>PMID:19783980</ref> <ref>PMID:20098430</ref> <ref>PMID:21423214</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 24:		Line 22:

	==See Also==		==See Also==
-	*[[Janus kinase\|Janus kinase]]	+	*[[Janus kinase 3D structures\|Janus kinase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Non-specific protein-tyrosine kinase]]~~	+	[[Category: Amboldi N]]
-	[[Category: Amboldi, N]]	+	[[Category: Avanzi N]]
-	[[Category: Avanzi, N]]	+	[[Category: Bertrand J]]
-	[[Category: Bertrand, J]]	+	[[Category: Bindi S]]
-	[[Category: Bindi, S]]	+	[[Category: Brasca MG]]
-	[[Category: Brasca~~, M G~~]]	+	[[Category: Canevari G]]
-	[[Category: Canevari, G]]	+	[[Category: Casero D]]
-	[[Category: Casero, D]]	+	[[Category: Ciomei M]]
-	[[Category: Ciomei, M]]	+	[[Category: Colombo N]]
-	[[Category: Colombo, N]]	+	[[Category: Cribioli S]]
-	[[Category: Cribioli, S]]	+	[[Category: Donati D]]
-	[[Category: Donati, D]]	+	[[Category: Fachin G]]
-	[[Category: Fachin, G]]	+	[[Category: Felder ER]]
-	[[Category: Felder~~, E R~~]]	+	[[Category: Galvani A]]
-	[[Category: Galvani, A]]	+	[[Category: Gnocchi P]]
-	[[Category: Gnocchi, P]]	+	[[Category: Isacchi A]]
-	[[Category: Isacchi, A]]	+	[[Category: Motto I]]
-	[[Category: Motto, I]]	+	[[Category: Nesi M]]
-	[[Category: Nesi, M]]	+	[[Category: Panzeri A]]
-	[[Category: Panzeri, A]]	+
-	~~[[Category: Anti-cancer agent]]~~	+
-	~~[[Category: Jak2]]~~	+
-	~~[[Category: Myeloproliferative disorder]]~~	+
-	~~[[Category: Protein kinase]]~~	+
-	~~[[Category: Transferase]]~~	+
-	~~[[Category: Tumour cell proliferation inhibition~~]]	+

OCA at 07:31, 24 April 2019

OCA — Wed, 24 Apr 2019 07:31:24 GMT

←Older revision		Revision as of 07:31, 24 April 2019
Line 1:		Line 1:

	==Novel pyrrole carboxamide inhibitors of JAK2 as potential treatment of myeloproliferative disorders==		==Novel pyrrole carboxamide inhibitors of JAK2 as potential treatment of myeloproliferative disorders==
-	<StructureSection load='5aep' size='340' side='right' caption='[[5aep]], [[Resolution\|resolution]] 1.95Å' scene=''>	+	<StructureSection load='5aep' size='340' side='right'caption='[[5aep]], [[Resolution\|resolution]] 1.95Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5aep]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5AEP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5AEP FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5aep]] is a 1 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=5AEP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5AEP FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=QUP:1-(5-CHLORO-2-METHYLPHENYL)-4-(PYRROLO[2,1-F][1,2,4]TRIAZIN-4-YL)-1H-PYRROLE-2-CARBOXAMIDE'>QUP</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=QUP:1-(5-CHLORO-2-METHYLPHENYL)-4-(PYRROLO[2,1-F][1,2,4]TRIAZIN-4-YL)-1H-PYRROLE-2-CARBOXAMIDE'>QUP</scene></td></tr>
	<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>		<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>
Line 29:		Line 29:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Non-specific protein-tyrosine kinase]]		[[Category: Non-specific protein-tyrosine kinase]]
	[[Category: Amboldi, N]]		[[Category: Amboldi, N]]

OCA at 06:23, 6 October 2017

OCA — Fri, 06 Oct 2017 06:23:59 GMT

←Older revision		Revision as of 06:23, 6 October 2017
Line 22:		Line 22:
	</div>		</div>
	<div class="pdbe-citations 5aep" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 5aep" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Janus kinase\|Janus kinase]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 09:56, 10 March 2017

OCA — Fri, 10 Mar 2017 09:56:32 GMT

←Older revision		Revision as of 09:56, 10 March 2017
Line 1:		Line 1:
		+
	==Novel pyrrole carboxamide inhibitors of JAK2 as potential treatment of myeloproliferative disorders==		==Novel pyrrole carboxamide inhibitors of JAK2 as potential treatment of myeloproliferative disorders==
	<StructureSection load='5aep' size='340' side='right' caption='[[5aep]], [[Resolution\|resolution]] 1.95Å' scene=''>		<StructureSection load='5aep' size='340' side='right' caption='[[5aep]], [[Resolution\|resolution]] 1.95Å' scene=''>
Line 6:		Line 7:
	<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>		<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </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=5aep FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5aep OCA], [http://www.rcsb.org/pdb/explore.do?structureId=5aep RCSB], [http://www.ebi.ac.uk/pdbsum/5aep 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=5aep FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5aep OCA], [http://pdbe.org/5aep PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5aep RCSB], [http://www.ebi.ac.uk/pdbsum/5aep PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5aep 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 5aep" style="background-color:#fffaf0;"></div>
	== References ==		== References ==
	<references/>		<references/>

OCA at 11:40, 30 April 2015

OCA — Thu, 30 Apr 2015 11:40:06 GMT

←Older revision		Revision as of 11:40, 30 April 2015
Line 1:		Line 1:
-	'''~~Unreleased~~ structure'''	+	==Novel pyrrole carboxamide inhibitors of JAK2 as potential treatment of myeloproliferative disorders==
		+	<StructureSection load='5aep' size='340' side='right' caption='[[5aep]], [[Resolution\|resolution]] 1.95Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5aep]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5AEP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5AEP FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=QUP:1-(5-CHLORO-2-METHYLPHENYL)-4-(PYRROLO[2,1-F][1,2,4]TRIAZIN-4-YL)-1H-PYRROLE-2-CARBOXAMIDE'>QUP</scene></td></tr>
		+	<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </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=5aep FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5aep OCA], [http://www.rcsb.org/pdb/explore.do?structureId=5aep RCSB], [http://www.ebi.ac.uk/pdbsum/5aep PDBsum]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/JAK2_HUMAN JAK2_HUMAN]] Note=Chromosomal aberrations involving JAK2 are found in both chronic and acute forms of eosinophilic, lymphoblastic and myeloid leukemia. Translocation t(8;9)(p22;p24) with PCM1 links the protein kinase domain of JAK2 to the major portion of PCM1. Translocation t(9;12)(p24;p13) with ETV6. Defects in JAK2 are a cause of susceptibility to Budd-Chiari syndrome (BDCHS) [MIM:[http://omim.org/entry/600880 600880]]. A syndrome caused by obstruction of hepatic venous outflow involving either the hepatic veins or the terminal segment of the inferior vena cava. Obstructions are generally caused by thrombosis and lead to hepatic congestion and ischemic necrosis. Clinical manifestations observed in the majority of patients include hepatomegaly, right upper quadrant pain and abdominal ascites. Budd-Chiari syndrome is associated with a combination of disease states including primary myeloproliferative syndromes and thrombophilia due to factor V Leiden, protein C deficiency and antithrombin III deficiency. Budd-Chiari syndrome is a rare but typical complication in patients with polycythemia vera. Defects in JAK2 are a cause of polycythemia vera (PV) [MIM:[http://omim.org/entry/263300 263300]]. A myeloproliferative disorder characterized by abnormal proliferation of all hematopoietic bone marrow elements, erythroid hyperplasia, an absolute increase in total blood volume, but also by myeloid leukocytosis, thrombocytosis and splenomegaly.<ref>PMID:15781101</ref> <ref>PMID:15793561</ref> <ref>PMID:15858187</ref> <ref>PMID:16603627</ref> Defects in JAK2 gene may be the cause of thrombocythemia type 3 (THCYT3) [MIM:[http://omim.org/entry/614521 614521]]. A myeloproliferative disorder characterized by elevated platelet levels due to sustained proliferation of megakaryocytes, and frequently lead to thrombotic and haemorrhagic complications.<ref>PMID:16325696</ref> <ref>PMID:22397670</ref> Defects in JAK2 are a cause of myelofibrosis (MYELOF) [MIM:[http://omim.org/entry/254450 254450]]. Myelofibrosis is a disorder characterized by replacement of the bone marrow by fibrous tissue, occurring in association with a myeloproliferative disorder. Clinical manifestations may include anemia, pallor, splenomegaly, hypermetabolic state, petechiae, ecchymosis, bleeding, lymphadenopathy, hepatomegaly, portal hypertension. Defects in JAK2 are a cause of acute myelogenous leukemia (AML) [MIM:[http://omim.org/entry/601626 601626]]. AML is a malignant disease in which hematopoietic precursors are arrested in an early stage of development.<ref>PMID:16247455</ref>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/JAK2_HUMAN JAK2_HUMAN]] Non-receptor tyrosine kinase involved in various processes such as cell growth, development, differentiation or histone modifications. Mediates essential signaling events in both innate and adaptive immunity. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors such as growth hormone (GHR), prolactin (PRLR), leptin (LEPR), erythropoietin (EPOR), thrombopoietin (THPO); or type II receptors including IFN-alpha, IFN-beta, IFN-gamma and multiple interleukins. Following ligand-binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins. Subsequently, phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then form homodimer or heterodimers and translocate to the nucleus to activate gene transcription. For example, cell stimulation with erythropoietin (EPO) during erythropoiesis leads to JAK2 autophosphorylation, activation, and its association with erythropoietin receptor (EPOR) that becomes phosphorylated in its cytoplasmic domain. Then, STAT5 (STAT5A or STAT5B) is recruited, phosphorylated and activated by JAK2. Once activated, dimerized STAT5 translocates into the nucleus and promotes the transcription of several essential genes involved in the modulation of erythropoiesis. In addition, JAK2 mediates angiotensin-2-induced ARHGEF1 phosphorylation. Plays a role in cell cycle by phosphorylating CDKN1B. Cooperates with TEC through reciprocal phosphorylation to mediate cytokine-driven activation of FOS transcription. In the nucleus, plays a key role in chromatin by specifically mediating phosphorylation of 'Tyr-41' of histone H3 (H3Y41ph), a specific tag that promotes exclusion of CBX5 (HP1 alpha) from chromatin.<ref>PMID:12023369</ref> <ref>PMID:19783980</ref> <ref>PMID:20098430</ref> <ref>PMID:21423214</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Compound 1, a hit from the screening of our chemical collection displaying activity against JAK2, was deconstructed for SAR analysis into three regions, which were explored. A series of compounds was synthesized leading to the identification of the potent and orally bioavailable JAK2 inhibitor 16 (NMS-P830), which showed an encouraging tumour growth inhibition in SET-2 xenograft tumour model, with evidence for JAK2 pathway suppression demonstrated by in vivo pharmacodynamic effects.

-	~~The entry 5aep is ON HOLD until Paper Publication~~	+	Novel pyrrole carboxamide inhibitors of JAK2 as potential treatment of myeloproliferative disorders.,Brasca MG, Gnocchi P, Nesi M, Amboldi N, Avanzi N, Bertrand J, Bindi S, Canevari G, Casero D, Ciomei M, Colombo N, Cribioli S, Fachin G, Felder ER, Galvani A, Isacchi A, Motto I, Panzeri A, Donati D Bioorg Med Chem. 2015 May 15;23(10):2387-407. doi: 10.1016/j.bmc.2015.03.059., Epub 2015 Mar 28. PMID:25882525<ref>PMID:25882525</ref>

-	~~Authors: Canevari~~, G.~~, Bertrand, J~~.~~, Brasca, M~~.~~G., Nesi, M.,~~ Amboldi, N., Avanzi, N~~., Bindi, S., Casero, D., Ciomei, M., Colombo, N., Cribioli, S., Fachin, G., Felder, E.R., Galvani, A., Isacchi, A., Motto, I., Panzeri, A., Gnocchi, P., Donati, D.~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-		+	</div>
-	~~Description~~: ~~Novel pyrrole carboxamide inhibitors of JAK2 as potential treatment of myeloproliferative disorders~~	+	== References ==
-	[[Category: ~~Unreleased Structures~~]]	+	<references/>
-	[[Category: ~~Ciomei~~, M]]	+	__TOC__
		+	</StructureSection>
		+	[[Category: Non-specific protein-tyrosine kinase]]
		+	[[Category: Amboldi, N]]
		+	[[Category: Avanzi, N]]
		+	[[Category: Bertrand, J]]
		+	[[Category: Bindi, S]]
		+	[[Category: Brasca, M G]]
	[[Category: Canevari, G]]		[[Category: Canevari, G]]
-	[[Category: Avanzi, N]]
-	[[Category: Amboldi, N]]
-	[[Category: Brasca, M.G]]
-	[[Category: Donati, D]]
	[[Category: Casero, D]]		[[Category: Casero, D]]
-	[[Category: ~~Felder~~, ~~E.R]]~~	+	[[Category: Ciomei, M]]
-	~~[[Category: Bertrand, J]]~~	+
-	~~[[Category: Gnocchi, P~~]]	+
	[[Category: Colombo, N]]		[[Category: Colombo, N]]
-	[[Category: ~~Panzeri~~, A]]	+	[[Category: Cribioli, S]]
-	[[Category: ~~Bindi~~, S]]	+	[[Category: Donati, D]]
		+	[[Category: Fachin, G]]
		+	[[Category: Felder, E R]]
	[[Category: Galvani, A]]		[[Category: Galvani, A]]
-	[[Category: ~~Cribioli~~, S]]	+	[[Category: Gnocchi, P]]
		+	[[Category: Isacchi, A]]
	[[Category: Motto, I]]		[[Category: Motto, I]]
-	[[Category: Isacchi, A]]
-	[[Category: Fachin, G]]
	[[Category: Nesi, M]]		[[Category: Nesi, M]]
		+	[[Category: Panzeri, A]]
		+	[[Category: Anti-cancer agent]]
		+	[[Category: Jak2]]
		+	[[Category: Myeloproliferative disorder]]
		+	[[Category: Protein kinase]]
		+	[[Category: Transferase]]
		+	[[Category: Tumour cell proliferation inhibition]]

OCA at 14:58, 7 February 2015

OCA — Sat, 07 Feb 2015 14:58:12 GMT

←Older revision		Revision as of 14:58, 7 February 2015
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 5aep is ON HOLD	+	The entry 5aep is ON HOLD until Paper Publication

	Authors: Canevari, G., Bertrand, J., Brasca, M.G., Nesi, M., Amboldi, N., Avanzi, N., Bindi, S., Casero, D., Ciomei, M., Colombo, N., Cribioli, S., Fachin, G., Felder, E.R., Galvani, A., Isacchi, A., Motto, I., Panzeri, A., Gnocchi, P., Donati, D.		Authors: Canevari, G., Bertrand, J., Brasca, M.G., Nesi, M., Amboldi, N., Avanzi, N., Bindi, S., Casero, D., Ciomei, M., Colombo, N., Cribioli, S., Fachin, G., Felder, E.R., Galvani, A., Isacchi, A., Motto, I., Panzeri, A., Gnocchi, P., Donati, D.

OCA: Protected "5aep" [edit=sysop:move=sysop]

OCA — Wed, 14 Jan 2015 12:49:37 GMT

Protected "5aep" [edit=sysop:move=sysop]

←Older revision

Revision as of 12:49, 14 January 2015

OCA: New page: '''Unreleased structure''' The entry 5aep is ON HOLD Authors: Canevari, G., Bertrand, J., Brasca, M.G., Nesi, M., Amboldi, N., Avanzi, N., Bindi, S., Casero, D., Ciomei, M., Colombo, N....

OCA — Wed, 14 Jan 2015 12:49:35 GMT

New page: '''Unreleased structure''' The entry 5aep is ON HOLD Authors: Canevari, G., Bertrand, J., Brasca, M.G., Nesi, M., Amboldi, N., Avanzi, N., Bindi, S., Casero, D., Ciomei, M., Colombo, N....

New page

'''Unreleased structure'''

The entry 5aep is ON HOLD

Authors: Canevari, G., Bertrand, J., Brasca, M.G., Nesi, M., Amboldi, N., Avanzi, N., Bindi, S., Casero, D., Ciomei, M., Colombo, N., Cribioli, S., Fachin, G., Felder, E.R., Galvani, A., Isacchi, A., Motto, I., Panzeri, A., Gnocchi, P., Donati, D.

Description: Novel pyrrole carboxamide inhibitors of JAK2 as potential treatment of myeloproliferative disorders
[[Category: Unreleased Structures]]
[[Category: Ciomei, M]]
[[Category: Canevari, G]]
[[Category: Avanzi, N]]
[[Category: Amboldi, N]]
[[Category: Brasca, M.G]]
[[Category: Donati, D]]
[[Category: Casero, D]]
[[Category: Felder, E.R]]
[[Category: Bertrand, J]]
[[Category: Gnocchi, P]]
[[Category: Colombo, N]]
[[Category: Panzeri, A]]
[[Category: Bindi, S]]
[[Category: Galvani, A]]
[[Category: Cribioli, S]]
[[Category: Motto, I]]
[[Category: Isacchi, A]]
[[Category: Fachin, G]]
[[Category: Nesi, M]]