4d0x - Revision history

OCA at 12:19, 20 December 2023

OCA — Wed, 20 Dec 2023 12:19:01 GMT

←Older revision		Revision as of 12:19, 20 December 2023
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4d0x]] 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=4D0X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4D0X FirstGlance]. <br>		<table><tr><td colspan='2'>[[4d0x]] 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=4D0X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4D0X FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=953:5-(2-AMINOPYRIMIDIN-4-YL)-2-[2-CHLORO-5-(TRIFLUOROMETHYL)PHENYL]-1H-PYRROLE-3-CARBOXAMIDE'>953</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</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]] 1.82Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=953:5-(2-AMINOPYRIMIDIN-4-YL)-2-[2-CHLORO-5-(TRIFLUOROMETHYL)PHENYL]-1H-PYRROLE-3-CARBOXAMIDE'>953</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <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=4d0x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d0x OCA], [https://pdbe.org/4d0x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4d0x RCSB], [https://www.ebi.ac.uk/pdbsum/4d0x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4d0x 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=4d0x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d0x OCA], [https://pdbe.org/4d0x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4d0x RCSB], [https://www.ebi.ac.uk/pdbsum/4d0x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4d0x ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
-	[[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>	+	[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 ==
-	[[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>	+	[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 ==

OCA at 07:41, 14 September 2022

OCA — Wed, 14 Sep 2022 07:41:59 GMT

←Older revision		Revision as of 07:41, 14 September 2022
Line 3:		Line 3:
	<StructureSection load='4d0x' size='340' side='right'caption='[[4d0x]], [[Resolution\|resolution]] 1.82Å' scene=''>		<StructureSection load='4d0x' size='340' side='right'caption='[[4d0x]], [[Resolution\|resolution]] 1.82Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4d0x]] 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=4D0X OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4D0X FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4d0x]] 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=4D0X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4D0X FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=953:5-(2-AMINOPYRIMIDIN-4-YL)-2-[2-CHLORO-5-(TRIFLUOROMETHYL)PHENYL]-1H-PYRROLE-3-CARBOXAMIDE'>953</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>~~</td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=953:5-(2-AMINOPYRIMIDIN-4-YL)-2-[2-CHLORO-5-(TRIFLUOROMETHYL)PHENYL]-1H-PYRROLE-3-CARBOXAMIDE'>953</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4d0x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d0x OCA], [https://pdbe.org/4d0x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4d0x RCSB], [https://www.ebi.ac.uk/pdbsum/4d0x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4d0x ProSAT]</span></td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4d0w\|4d0w]]</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=4d0x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d0x OCA], [~~http~~://pdbe.org/4d0x PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4d0x RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4d0x PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4d0x 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 25:		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: Avanzi N]]
-	[[Category: Avanzi, N]]	+	[[Category: Ballinari D]]
-	[[Category: Ballinari, D]]	+	[[Category: Bandiera T]]
-	[[Category: Bandiera, T]]	+	[[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: Carenzi D]]
-	[[Category: Carenzi, D]]	+	[[Category: Casero D]]
-	[[Category: Casero, D]]	+	[[Category: Ceriani L]]
-	[[Category: Ceriani, L]]	+	[[Category: Ciomei M]]
-	[[Category: Ciomei, M]]	+	[[Category: Cirla A]]
-	[[Category: Cirla, A]]	+	[[Category: Colombo M]]
-	[[Category: Colombo, M]]	+	[[Category: Cribioli S]]
-	[[Category: Cribioli, S]]	+	[[Category: Cristiani C]]
-	[[Category: Cristiani, C]]	+	[[Category: Della Vedova F]]
-	[[Category: Donati, D]]	+	[[Category: Donati D]]
-	[[Category: Fachin, G]]	+	[[Category: Fachin G]]
-	[[Category: Fasolini, M]]	+	[[Category: Fasolini M]]
-	[[Category: Felder~~, E R~~]]	+	[[Category: Felder ER]]
-	[[Category: Galvani, A]]	+	[[Category: Galvani A]]
-	[[Category: Gnocchi, P]]	+	[[Category: Gnocchi P]]
-	[[Category: Isacchi, A]]	+	[[Category: Isacchi A]]
-	[[Category: Mirizzi, D]]	+	[[Category: Mirizzi D]]
-	[[Category: Motto, I]]	+	[[Category: Motto I]]
-	[[Category: Nesi, M]]	+	[[Category: Nesi M]]
-	[[Category: Panzeri, A]]	+	[[Category: Panzeri A]]
-	[[Category: Pesenti, E]]	+	[[Category: Pesenti E]]
-	~~[[Category: Vedova, F Della~~]]	+	[[Category: Vianello P]]
-	[[Category: Vianello, P]]	+
-	~~[[Category: Anti-cancer agent]]~~	+
-	~~[[Category: Drug discovery]]~~	+
-	~~[[Category: Polycythemia vera]]~~	+
-	~~[[Category: Protein kinase inhibitor]]~~	+
-	~~[[Category: Structure-activity relationship]]~~	+
-	~~[[Category: Transferase]]~~	+
-	~~[[Category: Tumour cell proliferation inhibition~~]]	+

OCA at 07:28, 24 April 2019

OCA — Wed, 24 Apr 2019 07:28:09 GMT

←Older revision		Revision as of 07:28, 24 April 2019
Line 1:		Line 1:

	==Pyrrole-3-carboxamides as potent and selective JAK2 inhibitors==		==Pyrrole-3-carboxamides as potent and selective JAK2 inhibitors==
-	<StructureSection load='4d0x' size='340' side='right' caption='[[4d0x]], [[Resolution\|resolution]] 1.82Å' scene=''>	+	<StructureSection load='4d0x' size='340' side='right'caption='[[4d0x]], [[Resolution\|resolution]] 1.82Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4d0x]] 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=4D0X OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4D0X FirstGlance]. <br>		<table><tr><td colspan='2'>[[4d0x]] 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=4D0X OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4D0X FirstGlance]. <br>
Line 31:		Line 31:
	</StructureSection>		</StructureSection>
	[[Category: Human]]		[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Non-specific protein-tyrosine kinase]]		[[Category: Non-specific protein-tyrosine kinase]]
	[[Category: Avanzi, N]]		[[Category: Avanzi, N]]

OCA at 08:09, 6 March 2019

OCA — Wed, 06 Mar 2019 08:09:33 GMT

←Older revision		Revision as of 08:09, 6 March 2019
Line 1:		Line 1:

	==Pyrrole-3-carboxamides as potent and selective JAK2 inhibitors==		==Pyrrole-3-carboxamides as potent and selective JAK2 inhibitors==
-	<StructureSection load='4d0x' size='340' side='right' caption='[[4d0x]], [[Resolution\|resolution]] 1.82Å' scene=''>	+	<StructureSection load='4d0x' size='340' side='right' caption='[[4d0x]], [[Resolution\|resolution]] 1.82Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4d0x]] 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=4D0X OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4D0X FirstGlance]. <br>		<table><tr><td colspan='2'>[[4d0x]] 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=4D0X OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4D0X FirstGlance]. <br>
Line 23:		Line 23:
	</div>		</div>
	<div class="pdbe-citations 4d0x" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 4d0x" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Janus kinase\|Janus kinase]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 11:52, 6 November 2017

OCA — Mon, 06 Nov 2017 11:52:58 GMT

←Older revision		Revision as of 11:52, 6 November 2017
Line 3:		Line 3:
	<StructureSection load='4d0x' size='340' side='right' caption='[[4d0x]], [[Resolution\|resolution]] 1.82Å' scene=''>		<StructureSection load='4d0x' size='340' side='right' caption='[[4d0x]], [[Resolution\|resolution]] 1.82Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4d0x]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4D0X OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4D0X FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4d0x]] 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=4D0X OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4D0X FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=953:5-(2-AMINOPYRIMIDIN-4-YL)-2-[2-CHLORO-5-(TRIFLUOROMETHYL)PHENYL]-1H-PYRROLE-3-CARBOXAMIDE'>953</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=953:5-(2-AMINOPYRIMIDIN-4-YL)-2-[2-CHLORO-5-(TRIFLUOROMETHYL)PHENYL]-1H-PYRROLE-3-CARBOXAMIDE'>953</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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 23:		Line 23:
	</div>		</div>
	<div class="pdbe-citations 4d0x" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 4d0x" style="background-color:#fffaf0;"></div>
-
-	==See Also==
-	*[[Janus kinase\|Janus kinase]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Non-specific protein-tyrosine kinase]]		[[Category: Non-specific protein-tyrosine kinase]]
	[[Category: Avanzi, N]]		[[Category: Avanzi, N]]

OCA at 12:36, 11 August 2016

OCA — Thu, 11 Aug 2016 12:36:07 GMT

←Older revision		Revision as of 12:36, 11 August 2016
Line 1:		Line 1:
		+
	==Pyrrole-3-carboxamides as potent and selective JAK2 inhibitors==		==Pyrrole-3-carboxamides as potent and selective JAK2 inhibitors==
	<StructureSection load='4d0x' size='340' side='right' caption='[[4d0x]], [[Resolution\|resolution]] 1.82Å' scene=''>		<StructureSection load='4d0x' size='340' side='right' caption='[[4d0x]], [[Resolution\|resolution]] 1.82Å' scene=''>
Line 7:		Line 8:
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4d0w\|4d0w]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4d0w\|4d0w]]</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=4d0x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d0x OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4d0x RCSB], [http://www.ebi.ac.uk/pdbsum/4d0x 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=4d0x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d0x OCA], [http://pdbe.org/4d0x PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4d0x RCSB], [http://www.ebi.ac.uk/pdbsum/4d0x PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4d0x ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 21:		Line 22:
	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 4d0x" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Janus kinase\|Janus kinase]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 10:08, 20 January 2015

OCA — Tue, 20 Jan 2015 10:08:46 GMT

←Older revision		Revision as of 10:08, 20 January 2015
Line 3:		Line 3:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4d0x]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4D0X OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4D0X FirstGlance]. <br>		<table><tr><td colspan='2'>[[4d0x]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4D0X OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4D0X FirstGlance]. <br>
-	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=953:5-(2-AMINOPYRIMIDIN-4-YL)-2-[2-CHLORO-5-(TRIFLUOROMETHYL)PHENYL]-1H-PYRROLE-3-CARBOXAMIDE'>953</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene><br>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=953:5-(2-AMINOPYRIMIDIN-4-YL)-2-[2-CHLORO-5-(TRIFLUOROMETHYL)PHENYL]-1H-PYRROLE-3-CARBOXAMIDE'>953</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
-	<tr><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><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4d0w\|4d0w]]</td></tr>	+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4d0w\|4d0w]]</td></tr>
-	<tr><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><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4d0x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d0x OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4d0x RCSB], [http://www.ebi.ac.uk/pdbsum/4d0x 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=4d0x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d0x OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4d0x RCSB], [http://www.ebi.ac.uk/pdbsum/4d0x PDBsum]</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>		[[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>
Line 26:		Line 26:
	</StructureSection>		</StructureSection>
	[[Category: Non-specific protein-tyrosine kinase]]		[[Category: Non-specific protein-tyrosine kinase]]
-	[[Category: Avanzi, N.]]	+	[[Category: Avanzi, N]]
-	[[Category: Ballinari, D.]]	+	[[Category: Ballinari, D]]
-	[[Category: Bandiera, T.]]	+	[[Category: Bandiera, T]]
-	[[Category: Bertrand, J.]]	+	[[Category: Bertrand, J]]
-	[[Category: Bindi, S.]]	+	[[Category: Bindi, S]]
-	[[Category: Brasca, M G.]]	+	[[Category: Brasca, M G]]
-	[[Category: Canevari, G.]]	+	[[Category: Canevari, G]]
-	[[Category: Carenzi, D.]]	+	[[Category: Carenzi, D]]
-	[[Category: Casero, D.]]	+	[[Category: Casero, D]]
-	[[Category: Ceriani, L.]]	+	[[Category: Ceriani, L]]
-	[[Category: Ciomei, M.]]	+	[[Category: Ciomei, M]]
-	[[Category: Cirla, A.]]	+	[[Category: Cirla, A]]
-	[[Category: Colombo, M.]]	+	[[Category: Colombo, M]]
-	[[Category: Cribioli, S.]]	+	[[Category: Cribioli, S]]
-	[[Category: Cristiani, C.]]	+	[[Category: Cristiani, C]]
-	[[Category: Donati, D.]]	+	[[Category: Donati, D]]
-	[[Category: Fachin, G.]]	+	[[Category: Fachin, G]]
-	[[Category: Fasolini, M.]]	+	[[Category: Fasolini, M]]
-	[[Category: Felder, E R.]]	+	[[Category: Felder, E R]]
-	[[Category: Galvani, A.]]	+	[[Category: Galvani, A]]
-	[[Category: Gnocchi, P.]]	+	[[Category: Gnocchi, P]]
-	[[Category: Isacchi, A.]]	+	[[Category: Isacchi, A]]
-	[[Category: Mirizzi, D.]]	+	[[Category: Mirizzi, D]]
-	[[Category: Motto, I.]]	+	[[Category: Motto, I]]
-	[[Category: Nesi, M.]]	+	[[Category: Nesi, M]]
-	[[Category: Panzeri, A.]]	+	[[Category: Panzeri, A]]
-	[[Category: Pesenti, E.]]	+	[[Category: Pesenti, E]]
-	[[Category: Vedova, F Della.]]	+	[[Category: Vedova, F Della]]
-	[[Category: Vianello, P.]]	+	[[Category: Vianello, P]]
	[[Category: Anti-cancer agent]]		[[Category: Anti-cancer agent]]
	[[Category: Drug discovery]]		[[Category: Drug discovery]]

OCA at 08:01, 23 July 2014

OCA — Wed, 23 Jul 2014 08:01:29 GMT

←Older revision		Revision as of 08:01, 23 July 2014
Line 1:		Line 1:
-	'''~~Unreleased~~ structure'''	+	==Pyrrole-3-carboxamides as potent and selective JAK2 inhibitors==
		+	<StructureSection load='4d0x' size='340' side='right' caption='[[4d0x]], [[Resolution\|resolution]] 1.82Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[4d0x]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4D0X OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4D0X FirstGlance]. <br>
		+	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=953:5-(2-AMINOPYRIMIDIN-4-YL)-2-[2-CHLORO-5-(TRIFLUOROMETHYL)PHENYL]-1H-PYRROLE-3-CARBOXAMIDE'>953</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene><br>
		+	<tr><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><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4d0w\|4d0w]]</td></tr>
		+	<tr><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><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4d0x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d0x OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4d0x RCSB], [http://www.ebi.ac.uk/pdbsum/4d0x 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 ==
		+	We report herein the discovery, structure guided design, synthesis and biological evaluation of a novel class of JAK2 inhibitors. Optimization of the series led to the identification of the potent and orally bioavailable JAK2 inhibitor 28 (NMS-P953). Compound 28 displayed significant tumour growth inhibition in SET-2 xenograft tumour model, with a mechanism of action confirmed in vivo by typical modulation of known biomarkers, and with a favourable pharmacokinetic and safety profile.

-	~~The entry 4d0x is ON HOLD until Paper Publication~~	+	Pyrrole-3-carboxamides as potent and selective JAK2 inhibitors.,Brasca MG, Nesi M, Avanzi N, Ballinari D, Bandiera T, Bertrand J, Bindi S, Canevari G, Carenzi D, Casero D, Ceriani L, Ciomei M, Cirla A, Colombo M, Cribioli S, Cristiani C, Della Vedova F, Fachin G, Fasolini M, Felder ER, Galvani A, Isacchi A, Mirizzi D, Motto I, Panzeri A, Pesenti E, Vianello P, Gnocchi P, Donati D Bioorg Med Chem. 2014 Jun 21. pii: S0968-0896(14)00471-4. doi:, 10.1016/j.bmc.2014.06.025. PMID:25009002<ref>PMID:25009002</ref>

-	~~Authors: Canevari~~, G.~~, Fasolini, M~~.~~, Bertrand, J., Brasca, M~~.~~G., Nesi, M.,~~ Avanzi, N., Ballinari, D., Bandiera, T., Bindi, S., Carenzi, D., Casero, D., Ceriani, L., Ciomei, M., Cirla, A., Colombo, M., Cribioli, S., Cristiani, C., ~~Della Vedova, F~~., Fachin, G., Felder, E.R., Galvani, A., Isacchi, A., Mirizzi, D., Motto, I., Panzeri, A., Pesenti, E., Vianello, P.~~, Gnocchi, P., Donati, D.~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-		+	</div>
-	~~Description~~: ~~Pyrrole~~-~~3-carboxamides as potent and selective JAK2 inhibitors~~	+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Non-specific protein-tyrosine kinase]]
		+	[[Category: Avanzi, N.]]
		+	[[Category: Ballinari, D.]]
		+	[[Category: Bandiera, T.]]
		+	[[Category: Bertrand, J.]]
		+	[[Category: Bindi, S.]]
		+	[[Category: Brasca, M G.]]
		+	[[Category: Canevari, G.]]
		+	[[Category: Carenzi, D.]]
		+	[[Category: Casero, D.]]
		+	[[Category: Ceriani, L.]]
		+	[[Category: Ciomei, M.]]
		+	[[Category: Cirla, A.]]
		+	[[Category: Colombo, M.]]
		+	[[Category: Cribioli, S.]]
		+	[[Category: Cristiani, C.]]
		+	[[Category: Donati, D.]]
		+	[[Category: Fachin, G.]]
		+	[[Category: Fasolini, M.]]
		+	[[Category: Felder, E R.]]
		+	[[Category: Galvani, A.]]
		+	[[Category: Gnocchi, P.]]
		+	[[Category: Isacchi, A.]]
		+	[[Category: Mirizzi, D.]]
		+	[[Category: Motto, I.]]
		+	[[Category: Nesi, M.]]
		+	[[Category: Panzeri, A.]]
		+	[[Category: Pesenti, E.]]
		+	[[Category: Vedova, F Della.]]
		+	[[Category: Vianello, P.]]
		+	[[Category: Anti-cancer agent]]
		+	[[Category: Drug discovery]]
		+	[[Category: Polycythemia vera]]
		+	[[Category: Protein kinase inhibitor]]
		+	[[Category: Structure-activity relationship]]
		+	[[Category: Transferase]]
		+	[[Category: Tumour cell proliferation inhibition]]

OCA at 07:30, 21 May 2014

OCA — Wed, 21 May 2014 07:30:57 GMT

←Older revision		Revision as of 07:30, 21 May 2014
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 4d0x is ON HOLD	+	The entry 4d0x is ON HOLD until Paper Publication

	Authors: Canevari, G., Fasolini, M., Bertrand, J., Brasca, M.G., Nesi, M., Avanzi, N., Ballinari, D., Bandiera, T., Bindi, S., Carenzi, D., Casero, D., Ceriani, L., Ciomei, M., Cirla, A., Colombo, M., Cribioli, S., Cristiani, C., Della Vedova, F., Fachin, G., Felder, E.R., Galvani, A., Isacchi, A., Mirizzi, D., Motto, I., Panzeri, A., Pesenti, E., Vianello, P., Gnocchi, P., Donati, D.		Authors: Canevari, G., Fasolini, M., Bertrand, J., Brasca, M.G., Nesi, M., Avanzi, N., Ballinari, D., Bandiera, T., Bindi, S., Carenzi, D., Casero, D., Ceriani, L., Ciomei, M., Cirla, A., Colombo, M., Cribioli, S., Cristiani, C., Della Vedova, F., Fachin, G., Felder, E.R., Galvani, A., Isacchi, A., Mirizzi, D., Motto, I., Panzeri, A., Pesenti, E., Vianello, P., Gnocchi, P., Donati, D.

	Description: Pyrrole-3-carboxamides as potent and selective JAK2 inhibitors		Description: Pyrrole-3-carboxamides as potent and selective JAK2 inhibitors

OCA: Protected "4d0x" [edit=sysop:move=sysop]

OCA — Wed, 07 May 2014 07:24:38 GMT

Protected "4d0x" [edit=sysop:move=sysop]

←Older revision

Revision as of 07:24, 7 May 2014