4e6d - Revision history

OCA at 10:47, 6 November 2024

2024-11-06T10:47:31Z

← Older revision		Revision as of 10:47, 6 November 2024
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4e6d]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4E6D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4E6D FirstGlance]. <br>		<table><tr><td colspan='2'>[[4e6d]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4E6D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4E6D FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0NU:3-[(3R)-3-(IMIDAZO[4,5-D]PYRROLO[2,3-B]PYRIDIN-1(6H)-YL)PIPERIDIN-1-YL]-3-OXOPROPANENITRILE'>0NU</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]] 2.22Å</td></tr>
			<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0NU:3-[(3R)-3-(IMIDAZO[4,5-D]PYRROLO[2,3-B]PYRIDIN-1(6H)-YL)PIPERIDIN-1-YL]-3-OXOPROPANENITRILE'>0NU</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=4e6d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4e6d OCA], [https://pdbe.org/4e6d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4e6d RCSB], [https://www.ebi.ac.uk/pdbsum/4e6d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4e6d 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=4e6d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4e6d OCA], [https://pdbe.org/4e6d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4e6d RCSB], [https://www.ebi.ac.uk/pdbsum/4e6d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4e6d ProSAT]</span></td></tr>
	</table>		</table>

OCA at 06:06, 2 March 2023

2023-03-02T06:06:56Z

← Older revision		Revision as of 06:06, 2 March 2023
Line 8:		Line 8:
	</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 06:53, 28 September 2022

2022-09-28T06:53:26Z

← Older revision		Revision as of 06:53, 28 September 2022
Line 1:		Line 1:

	==JAK2 kinase (JH1 domain) triple mutant in complex with compound 7==		==JAK2 kinase (JH1 domain) triple mutant in complex with compound 7==
	<StructureSection load='4e6d' size='340' side='right' caption='[[4e6d]], [[Resolution\|resolution]] 2.22Å' scene=''>		<StructureSection load='4e6d' size='340' side='right'caption='[[4e6d]], [[Resolution\|resolution]] 2.22Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4e6d]] is a 2 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4E6D OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4E6D FirstGlance]. <br>		<table><tr><td colspan='2'>[[4e6d]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4E6D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4E6D FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0NU:3-[(3R)-3-(IMIDAZO[4,5-D]PYRROLO[2,3-B]PYRIDIN-1(6H)-YL)PIPERIDIN-1-YL]-3-OXOPROPANENITRILE'>0NU</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=0NU:3-[(3R)-3-(IMIDAZO[4,5-D]PYRROLO[2,3-B]PYRIDIN-1(6H)-YL)PIPERIDIN-1-YL]-3-OXOPROPANENITRILE'>0NU</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=4e6d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4e6d OCA], [https://pdbe.org/4e6d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4e6d RCSB], [https://www.ebi.ac.uk/pdbsum/4e6d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4e6d ProSAT]</span></td></tr>
	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4e4l\|4e4l]], [[4e4m\|4e4m]], [[4e4n\|4e4n]], [[4e5w\|4e5w]], [[4e6q\|4e6q]]</td></tr>~~
	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">JAK2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4e6d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4e6d OCA], [~~http~~://pdbe.org/4e6d PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4e6d RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4e6d PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4e6d 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 26:		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: ~~Non-specific protein-tyrosine kinase~~]]		[[Category: Large Structures]]
	[[Category: Murray~~, J M]]~~		[[Category: Murray JM]]
	~~[[Category: Jak2]]~~
	~~[[Category: Kinase]]~~
	~~[[Category: Phosphorylation]]~~
	~~[[Category: Transferase]]~~
	~~[[Category: Transferase-transferase inhibitor complex~~]]

OCA at 08:13, 5 August 2016

2016-08-05T08:13:07Z

← Older revision		Revision as of 08:13, 5 August 2016
Line 1:		Line 1:

	==JAK2 kinase (JH1 domain) triple mutant in complex with compound 7==		==JAK2 kinase (JH1 domain) triple mutant in complex with compound 7==
	<StructureSection load='4e6d' size='340' side='right' caption='[[4e6d]], [[Resolution\|resolution]] 2.22Å' scene=''>		<StructureSection load='4e6d' size='340' side='right' caption='[[4e6d]], [[Resolution\|resolution]] 2.22Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4e6d]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/~~Homo_sapiens Homo sapiens~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4E6D OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4E6D FirstGlance]. <br>		<table><tr><td colspan='2'>[[4e6d]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4E6D OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4E6D FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0NU:3-[(3R)-3-(IMIDAZO[4,5-D]PYRROLO[2,3-B]PYRIDIN-1(6H)-YL)PIPERIDIN-1-YL]-3-OXOPROPANENITRILE'>0NU</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=0NU:3-[(3R)-3-(IMIDAZO[4,5-D]PYRROLO[2,3-B]PYRIDIN-1(6H)-YL)PIPERIDIN-1-YL]-3-OXOPROPANENITRILE'>0NU</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>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4e4l\|4e4l]], [[4e4m\|4e4m]], [[4e4n\|4e4n]], [[4e5w\|4e5w]], [[4e6q\|4e6q]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4e4l\|4e4l]], [[4e4m\|4e4m]], [[4e4n\|4e4n]], [[4e5w\|4e5w]], [[4e6q\|4e6q]]</td></tr>
	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">JAK2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 ~~Homo sapiens~~])</td></tr>		<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">JAK2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4e6d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4e6d OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4e6d RCSB], [http://www.ebi.ac.uk/pdbsum/4e6d 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=4e6d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4e6d OCA], [http://pdbe.org/4e6d PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4e6d RCSB], [http://www.ebi.ac.uk/pdbsum/4e6d PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4e6d ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 22:		Line 23:
	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 4e6d" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
Line 29:		Line 31:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: ~~Homo sapiens~~]]		[[Category: Human]]
	[[Category: Non-specific protein-tyrosine kinase]]		[[Category: Non-specific protein-tyrosine kinase]]
	[[Category: Murray, J M]]		[[Category: Murray, J M]]

OCA at 10:57, 21 December 2014

2014-12-21T10:57:12Z

← Older revision		Revision as of 10:57, 21 December 2014
Line 1:		Line 1:
	~~{{STRUCTURE_4e6d~~\| ~~PDB~~=4e6d \| ~~SCENE=~~ }}		==JAK2 kinase (JH1 domain) triple mutant in complex with compound 7==
	===JAK2 ~~kinase~~ (~~JH1~~ domain) ~~triple mutant~~ in ~~complex~~ with ~~compound 7~~===		<StructureSection load='4e6d' size='340' side='right' caption='[[4e6d]], [[Resolution\|resolution]] 2.22Å' scene=''>
	~~{{ABSTRACT_PUBMED_22591402}}~~		== Structural highlights ==
			<table><tr><td colspan='2'>[[4e6d]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4E6D OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4E6D FirstGlance]. <br>
			</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0NU:3-[(3R)-3-(IMIDAZO[4,5-D]PYRROLO[2,3-B]PYRIDIN-1(6H)-YL)PIPERIDIN-1-YL]-3-OXOPROPANENITRILE'>0NU</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='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4e4l\|4e4l]], [[4e4m\|4e4m]], [[4e4n\|4e4n]], [[4e5w\|4e5w]], [[4e6q\|4e6q]]</td></tr>
			<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">JAK2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=4e6d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4e6d OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4e6d RCSB], [http://www.ebi.ac.uk/pdbsum/4e6d 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 ==
			A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as rheumatoid arthritis (RA), by specific targeting of the JAK1 pathway. Examination of the preferred binding conformation of clinically effective, pan-JAK inhibitor 1 led to identification of a novel, tricyclic hinge binding scaffold 3. Exploration of SAR through a series of cycloamino and cycloalkylamino analogs demonstrated this template to be highly tolerant of substitution, with a predisposition to moderate selectivity for the JAK1 isoform over JAK2. This study culminated in the identification of sub-nanomolar JAK1 inhibitors such as 22 and 49, having excellent cell potency, good rat pharmacokinetic characteristics, and excellent kinase selectivity. Determination of the binding modes of the series in JAK1 and JAK2 by X-ray crystallography supported the design of analogs to enhance affinity and selectivity.

	~~==Disease==~~		Identification of Imidazo-pyrrolopyridines as Novel and Potent JAK1 Inhibitors.,Kulagowski J J Med Chem. 2012 May 16. PMID:22591402<ref>PMID:22591402</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>

	~~==Function==~~		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	~~[[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>

	==~~About this Structure~~==		==See Also==
	[[~~4e6d~~]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4E6D OCA].		*[[Janus kinase\|Janus kinase]]
			== References ==
	==~~Reference~~==		<references/>
	~~<ref group="xtra">PMID:022591402</ref>~~<references ~~group="xtra"~~/><~~references~~/>		__TOC__
			</StructureSection>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Non-specific protein-tyrosine kinase]]		[[Category: Non-specific protein-tyrosine kinase]]
	[[Category: Murray, J M.]]		[[Category: Murray, J M]]
	[[Category: Jak2]]		[[Category: Jak2]]
	[[Category: Kinase]]		[[Category: Kinase]]

OCA at 18:21, 24 March 2013

2013-03-24T18:21:59Z

← Older revision		Revision as of 18:21, 24 March 2013
Line 1:		Line 1:
	~~[[Image:4e6d.png\|left\|200px]]~~

	{{STRUCTURE_4e6d\| PDB=4e6d \| SCENE= }}		{{STRUCTURE_4e6d\| PDB=4e6d \| SCENE= }}
			===JAK2 kinase (JH1 domain) triple mutant in complex with compound 7===
			{{ABSTRACT_PUBMED_22591402}}

	===JAK2 kinase (~~JH1 domain~~) ~~triple mutant~~ in ~~complex~~ with ~~compound 7===~~		==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>

	~~{{ABSTRACT_PUBMED_22591402}}~~		==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>

	==About this Structure==		==About this Structure==
Line 11:		Line 13:

	==Reference==		==Reference==
	<ref group="xtra">PMID:022591402</ref><references group="xtra"/>		<ref group="xtra">PMID:022591402</ref><references group="xtra"/><references/>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Non-specific protein-tyrosine kinase]]		[[Category: Non-specific protein-tyrosine kinase]]

OCA at 07:30, 11 July 2012

2012-07-11T07:30:29Z

← Older revision		Revision as of 07:30, 11 July 2012
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	[[Image:4e6d.png\|left\|200px]]		[[Image:4e6d.png\|left\|200px]]

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	{{STRUCTURE_4e6d\| PDB=4e6d \| SCENE= }}		{{STRUCTURE_4e6d\| PDB=4e6d \| SCENE= }}

	===JAK2 kinase (JH1 domain) triple mutant in complex with compound 7===		===JAK2 kinase (JH1 domain) triple mutant in complex with compound 7===


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	{{ABSTRACT_PUBMED_22591402}}		{{ABSTRACT_PUBMED_22591402}}

OCA at 05:27, 13 June 2012

2012-06-13T05:27:10Z

← Older revision		Revision as of 05:27, 13 June 2012
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	[[Image:4e6d.~~jpg~~\|left\|200px]]		[[Image:4e6d.png\|left\|200px]]

	<!--		<!--
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	{{STRUCTURE_4e6d\| PDB=4e6d \| SCENE= }}		{{STRUCTURE_4e6d\| PDB=4e6d \| SCENE= }}

	===~~AK2~~ kinase (JH1 domain) triple mutant in complex with compound 7===		===JAK2 kinase (JH1 domain) triple mutant in complex with compound 7===

OCA at 05:55, 30 May 2012

2012-05-30T05:55:48Z

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-'''Unreleased structure'''
+[[Image:4e6d.jpg|left|200px]]
-The entry 4e6d is ON HOLD
+<!--
-Authors: Murray, J.M.
+===AK2 kinase (JH1 domain) triple mutant in complex with compound 7===
-Description: Novel and Potent JAK1 Inhibitors

OCA: Protected "4e6d" [edit=sysop:move=sysop]

2012-03-21T07:18:54Z

Protected "4e6d" [edit=sysop:move=sysop]

← Older revision	Revision as of 07:18, 21 March 2012
(No difference)