4bbf - Revision history

OCA at 07:17, 1 May 2024

2024-05-01T07:17:32Z

← Older revision		Revision as of 07:17, 1 May 2024
Line 3:		Line 3:
	<StructureSection load='4bbf' size='340' side='right'caption='[[4bbf]], [[Resolution\|resolution]] 2.00Å' scene=''>		<StructureSection load='4bbf' size='340' side='right'caption='[[4bbf]], [[Resolution\|resolution]] 2.00Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4bbf]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BBF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BBF FirstGlance]. <br>		<table><tr><td colspan='2'>[[4bbf]] is a 4 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=4BBF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BBF FirstGlance]. <br>
	</td></tr><tr id='~~ligand~~'><td class="sblockLbl"><b>[[~~Ligand~~\|~~Ligands~~:]]</b></td><td class="sblockDat" id="~~ligandDat~~">~~<scene name='pdbligand=O19:(2R)-N~~-[4-[~~2-[(4-MORPHOLIN-4-YLPHENYL)AMINO]PYRIMIDIN-4-YL~~]~~PHENYL~~]~~PYRROLIDINE-~~2~~-CARBOXAMIDE'>O19</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]] 2Å</td></tr>
	<tr id='~~related~~'><td class="sblockLbl"><b>[[~~Related_structure~~\|~~Related~~:]]</b></td><td class="sblockDat"><~~div style~~='~~overflow~~: ~~auto; max~~-~~height: 3em;'>~~[[~~2b7a\|2b7a]],~~ [~~[2w1i\|2w1i]], [[2xa4\|2xa4]], [[4aqc\|4aqc]], [[4bbe\|4bbe]]</div></td></tr>~~		<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=O19:(2R)-N-[4-[2-[(4-MORPHOLIN-4-YLPHENYL)AMINO]PYRIMIDIN-4-YL]PHENYL]PYRROLIDINE-2-CARBOXAMIDE'>O19</scene></td></tr>
	~~<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Non~~-~~specific_protein~~-~~tyrosine_kinase Non~~-~~specific protein~~-~~tyrosine kinase~~]~~, with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=4bbf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bbf OCA], [https://pdbe.org/4bbf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bbf RCSB], [https://www.ebi.ac.uk/pdbsum/4bbf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bbf 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=4bbf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bbf OCA], [https://pdbe.org/4bbf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bbf RCSB], [https://www.ebi.ac.uk/pdbsum/4bbf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bbf 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;">~~
	~~== Publication Abstract from PubMed ==~~
	We report the discovery of a series of 4-aryl-2-aminoalkylpyrimidine derivatives as potent and selective JAK2 inhibitors. High throughput screening of our in-house compound library led to the identification of hit 1, from which optimization resulted in the discovery of highly potent and selective JAK2 inhibitors. Advanced lead 10d demonstrated a significant dose-dependent pharmacodynamic and antitumor effect in a mouse xenograft model. Based upon the desirable profile of 10d (XL019) it was advanced into clinical trials.

	SAR and in vivo evaluation of 4-aryl-2-aminoalkylpyrimidines as potent and selective Janus kinase 2 (JAK2) inhibitors.,Forsyth T, Kearney PC, Kim BG, Johnson HW, Aay N, Arcalas A, Brown DS, Chan V, Chen J, Du H, Epshteyn S, Galan AA, Huynh TP, Ibrahim MA, Kane B, Koltun ES, Mann G, Meyr LE, Lee MS, Lewis GL, Noguchi RT, Pack M, Ridgway BH, Shi X, Takeuchi CS, Zu P, Leahy JW, Nuss JM, Aoyama R, Engst S, Gendreau SB, Kassees R, Li J, Lin SH, Martini JF, Stout T, Tong P, Woolfrey J, Zhang W, Yu P Bioorg Med Chem Lett. 2012 Oct 16. pii: S0960-894X(12)01274-7. doi:, 10.1016/j.bmcl.2012.10.007. PMID:23127890<ref>PMID:23127890</ref>

	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~
	~~</div>~~
	~~<div class="pdbe-citations 4bbf" style="background-color:#fffaf0;"></div~~>

	==See Also==		==See Also==
Line 29:		Line 19:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
			[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	~~[[Category: Non-specific protein-tyrosine kinase]]~~		[[Category: Li J]]
	[[Category: Li, J]]
	~~[[Category: Inhibitor]]~~
	~~[[Category: Transferase~~]]

OCA at 07:06, 31 August 2022

2022-08-31T07:06:48Z

← Older revision		Revision as of 07:06, 31 August 2022
Line 3:		Line 3:
	<StructureSection load='4bbf' size='340' side='right'caption='[[4bbf]], [[Resolution\|resolution]] 2.00Å' scene=''>		<StructureSection load='4bbf' size='340' side='right'caption='[[4bbf]], [[Resolution\|resolution]] 2.00Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4bbf]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BBF OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4BBF FirstGlance]. <br>		<table><tr><td colspan='2'>[[4bbf]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BBF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BBF FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=O19:(2R)-N-[4-[2-[(4-MORPHOLIN-4-YLPHENYL)AMINO]PYRIMIDIN-4-YL]PHENYL]PYRROLIDINE-2-CARBOXAMIDE'>O19</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=O19:(2R)-N-[4-[2-[(4-MORPHOLIN-4-YLPHENYL)AMINO]PYRIMIDIN-4-YL]PHENYL]PYRROLIDINE-2-CARBOXAMIDE'>O19</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2b7a\|2b7a]], [[2w1i\|2w1i]], [[2xa4\|2xa4]], [[4aqc\|4aqc]], [[4bbe\|4bbe]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[2b7a\|2b7a]], [[2w1i\|2w1i]], [[2xa4\|2xa4]], [[4aqc\|4aqc]], [[4bbe\|4bbe]]</div></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'>[https://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [https://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=4bbf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bbf OCA], [~~http~~://pdbe.org/4bbf PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4bbf RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4bbf PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4bbf 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=4bbf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bbf OCA], [https://pdbe.org/4bbf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bbf RCSB], [https://www.ebi.ac.uk/pdbsum/4bbf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bbf ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
	[[~~http~~://www.uniprot.org/uniprot/JAK2_HUMAN JAK2_HUMAN]] Note=Chromosomal aberrations involving JAK2 are found in both chronic and acute forms of eosinophilic, lymphoblastic and myeloid leukemia. Translocation t(8;9)(p22;p24) with PCM1 links the protein kinase domain of JAK2 to the major portion of PCM1. Translocation t(9;12)(p24;p13) with ETV6. Defects in JAK2 are a cause of susceptibility to Budd-Chiari syndrome (BDCHS) [MIM:[~~http~~://omim.org/entry/600880 600880]]. A syndrome caused by obstruction of hepatic venous outflow involving either the hepatic veins or the terminal segment of the inferior vena cava. Obstructions are generally caused by thrombosis and lead to hepatic congestion and ischemic necrosis. Clinical manifestations observed in the majority of patients include hepatomegaly, right upper quadrant pain and abdominal ascites. Budd-Chiari syndrome is associated with a combination of disease states including primary myeloproliferative syndromes and thrombophilia due to factor V Leiden, protein C deficiency and antithrombin III deficiency. Budd-Chiari syndrome is a rare but typical complication in patients with polycythemia vera. Defects in JAK2 are a cause of polycythemia vera (PV) [MIM:[~~http~~://omim.org/entry/263300 263300]]. A myeloproliferative disorder characterized by abnormal proliferation of all hematopoietic bone marrow elements, erythroid hyperplasia, an absolute increase in total blood volume, but also by myeloid leukocytosis, thrombocytosis and splenomegaly.<ref>PMID:15781101</ref> <ref>PMID:15793561</ref> <ref>PMID:15858187</ref> <ref>PMID:16603627</ref> Defects in JAK2 gene may be the cause of thrombocythemia type 3 (THCYT3) [MIM:[~~http~~://omim.org/entry/614521 614521]]. A myeloproliferative disorder characterized by elevated platelet levels due to sustained proliferation of megakaryocytes, and frequently lead to thrombotic and haemorrhagic complications.<ref>PMID:16325696</ref> <ref>PMID:22397670</ref> Defects in JAK2 are a cause of myelofibrosis (MYELOF) [MIM:[~~http~~://omim.org/entry/254450 254450]]. Myelofibrosis is a disorder characterized by replacement of the bone marrow by fibrous tissue, occurring in association with a myeloproliferative disorder. Clinical manifestations may include anemia, pallor, splenomegaly, hypermetabolic state, petechiae, ecchymosis, bleeding, lymphadenopathy, hepatomegaly, portal hypertension. Defects in JAK2 are a cause of acute myelogenous leukemia (AML) [MIM:[~~http~~://omim.org/entry/601626 601626]]. AML is a malignant disease in which hematopoietic precursors are arrested in an early stage of development.<ref>PMID:16247455</ref>		[[https://www.uniprot.org/uniprot/JAK2_HUMAN JAK2_HUMAN]] Note=Chromosomal aberrations involving JAK2 are found in both chronic and acute forms of eosinophilic, lymphoblastic and myeloid leukemia. Translocation t(8;9)(p22;p24) with PCM1 links the protein kinase domain of JAK2 to the major portion of PCM1. Translocation t(9;12)(p24;p13) with ETV6. Defects in JAK2 are a cause of susceptibility to Budd-Chiari syndrome (BDCHS) [MIM:[https://omim.org/entry/600880 600880]]. A syndrome caused by obstruction of hepatic venous outflow involving either the hepatic veins or the terminal segment of the inferior vena cava. Obstructions are generally caused by thrombosis and lead to hepatic congestion and ischemic necrosis. Clinical manifestations observed in the majority of patients include hepatomegaly, right upper quadrant pain and abdominal ascites. Budd-Chiari syndrome is associated with a combination of disease states including primary myeloproliferative syndromes and thrombophilia due to factor V Leiden, protein C deficiency and antithrombin III deficiency. Budd-Chiari syndrome is a rare but typical complication in patients with polycythemia vera. Defects in JAK2 are a cause of polycythemia vera (PV) [MIM:[https://omim.org/entry/263300 263300]]. A myeloproliferative disorder characterized by abnormal proliferation of all hematopoietic bone marrow elements, erythroid hyperplasia, an absolute increase in total blood volume, but also by myeloid leukocytosis, thrombocytosis and splenomegaly.<ref>PMID:15781101</ref> <ref>PMID:15793561</ref> <ref>PMID:15858187</ref> <ref>PMID:16603627</ref> Defects in JAK2 gene may be the cause of thrombocythemia type 3 (THCYT3) [MIM:[https://omim.org/entry/614521 614521]]. A myeloproliferative disorder characterized by elevated platelet levels due to sustained proliferation of megakaryocytes, and frequently lead to thrombotic and haemorrhagic complications.<ref>PMID:16325696</ref> <ref>PMID:22397670</ref> Defects in JAK2 are a cause of myelofibrosis (MYELOF) [MIM:[https://omim.org/entry/254450 254450]]. Myelofibrosis is a disorder characterized by replacement of the bone marrow by fibrous tissue, occurring in association with a myeloproliferative disorder. Clinical manifestations may include anemia, pallor, splenomegaly, hypermetabolic state, petechiae, ecchymosis, bleeding, lymphadenopathy, hepatomegaly, portal hypertension. Defects in JAK2 are a cause of acute myelogenous leukemia (AML) [MIM:[https://omim.org/entry/601626 601626]]. AML is a malignant disease in which hematopoietic precursors are arrested in an early stage of development.<ref>PMID:16247455</ref>
	== Function ==		== Function ==
	[[~~http~~://www.uniprot.org/uniprot/JAK2_HUMAN JAK2_HUMAN]] Non-receptor tyrosine kinase involved in various processes such as cell growth, development, differentiation or histone modifications. Mediates essential signaling events in both innate and adaptive immunity. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors such as growth hormone (GHR), prolactin (PRLR), leptin (LEPR), erythropoietin (EPOR), thrombopoietin (THPO); or type II receptors including IFN-alpha, IFN-beta, IFN-gamma and multiple interleukins. Following ligand-binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins. Subsequently, phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then form homodimer or heterodimers and translocate to the nucleus to activate gene transcription. For example, cell stimulation with erythropoietin (EPO) during erythropoiesis leads to JAK2 autophosphorylation, activation, and its association with erythropoietin receptor (EPOR) that becomes phosphorylated in its cytoplasmic domain. Then, STAT5 (STAT5A or STAT5B) is recruited, phosphorylated and activated by JAK2. Once activated, dimerized STAT5 translocates into the nucleus and promotes the transcription of several essential genes involved in the modulation of erythropoiesis. In addition, JAK2 mediates angiotensin-2-induced ARHGEF1 phosphorylation. Plays a role in cell cycle by phosphorylating CDKN1B. Cooperates with TEC through reciprocal phosphorylation to mediate cytokine-driven activation of FOS transcription. In the nucleus, plays a key role in chromatin by specifically mediating phosphorylation of 'Tyr-41' of histone H3 (H3Y41ph), a specific tag that promotes exclusion of CBX5 (HP1 alpha) from chromatin.<ref>PMID:12023369</ref> <ref>PMID:19783980</ref> <ref>PMID:20098430</ref> <ref>PMID:21423214</ref>		[[https://www.uniprot.org/uniprot/JAK2_HUMAN JAK2_HUMAN]] Non-receptor tyrosine kinase involved in various processes such as cell growth, development, differentiation or histone modifications. Mediates essential signaling events in both innate and adaptive immunity. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors such as growth hormone (GHR), prolactin (PRLR), leptin (LEPR), erythropoietin (EPOR), thrombopoietin (THPO); or type II receptors including IFN-alpha, IFN-beta, IFN-gamma and multiple interleukins. Following ligand-binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins. Subsequently, phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then form homodimer or heterodimers and translocate to the nucleus to activate gene transcription. For example, cell stimulation with erythropoietin (EPO) during erythropoiesis leads to JAK2 autophosphorylation, activation, and its association with erythropoietin receptor (EPOR) that becomes phosphorylated in its cytoplasmic domain. Then, STAT5 (STAT5A or STAT5B) is recruited, phosphorylated and activated by JAK2. Once activated, dimerized STAT5 translocates into the nucleus and promotes the transcription of several essential genes involved in the modulation of erythropoiesis. In addition, JAK2 mediates angiotensin-2-induced ARHGEF1 phosphorylation. Plays a role in cell cycle by phosphorylating CDKN1B. Cooperates with TEC through reciprocal phosphorylation to mediate cytokine-driven activation of FOS transcription. In the nucleus, plays a key role in chromatin by specifically mediating phosphorylation of 'Tyr-41' of histone H3 (H3Y41ph), a specific tag that promotes exclusion of CBX5 (HP1 alpha) from chromatin.<ref>PMID:12023369</ref> <ref>PMID:19783980</ref> <ref>PMID:20098430</ref> <ref>PMID:21423214</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 24:		Line 24:

	==See Also==		==See Also==
	*[[Janus kinase\|Janus kinase]]		*[[Janus kinase 3D structures\|Janus kinase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 18:06, 14 August 2019

2019-08-14T18:06:20Z

← Older revision		Revision as of 18:06, 14 August 2019
Line 1:		Line 1:

	==Aminoalkylpyrimidine Inhibitor Complexes with JAK2==		==Aminoalkylpyrimidine Inhibitor Complexes with JAK2==
	<StructureSection load='4bbf' size='340' side='right' caption='[[4bbf]], [[Resolution\|resolution]] 2.00Å' scene=''>		<StructureSection load='4bbf' size='340' side='right'caption='[[4bbf]], [[Resolution\|resolution]] 2.00Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4bbf]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BBF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BBF FirstGlance]. <br>		<table><tr><td colspan='2'>[[4bbf]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BBF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BBF FirstGlance]. <br>
Line 22:		Line 22:
	</div>		</div>
	<div class="pdbe-citations 4bbf" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 4bbf" style="background-color:#fffaf0;"></div>

			==See Also==
			*[[Janus kinase\|Janus kinase]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
			[[Category: Large Structures]]
	[[Category: Non-specific protein-tyrosine kinase]]		[[Category: Non-specific protein-tyrosine kinase]]
	[[Category: Li, J]]		[[Category: Li, J]]
	[[Category: Inhibitor]]		[[Category: Inhibitor]]
	[[Category: Transferase]]		[[Category: Transferase]]

OCA at 12:30, 6 November 2017

2017-11-06T12:30:15Z

← Older revision		Revision as of 12:30, 6 November 2017
Line 22:		Line 22:
	</div>		</div>
	<div class="pdbe-citations 4bbf" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 4bbf" style="background-color:#fffaf0;"></div>

	~~==See Also==~~
	*[[Janus kinase\|Janus kinase]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 09:23, 3 August 2017

2017-08-03T09:23:57Z

← Older revision		Revision as of 09:23, 3 August 2017
Line 3:		Line 3:
	<StructureSection load='4bbf' size='340' side='right' caption='[[4bbf]], [[Resolution\|resolution]] 2.00Å' scene=''>		<StructureSection load='4bbf' size='340' side='right' caption='[[4bbf]], [[Resolution\|resolution]] 2.00Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4bbf]] is a 4 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=4BBF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BBF FirstGlance]. <br>		<table><tr><td colspan='2'>[[4bbf]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BBF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BBF FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=O19:(2R)-N-[4-[2-[(4-MORPHOLIN-4-YLPHENYL)AMINO]PYRIMIDIN-4-YL]PHENYL]PYRROLIDINE-2-CARBOXAMIDE'>O19</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=O19:(2R)-N-[4-[2-[(4-MORPHOLIN-4-YLPHENYL)AMINO]PYRIMIDIN-4-YL]PHENYL]PYRROLIDINE-2-CARBOXAMIDE'>O19</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2b7a\|2b7a]], [[2w1i\|2w1i]], [[2xa4\|2xa4]], [[4aqc\|4aqc]], [[4bbe\|4bbe]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2b7a\|2b7a]], [[2w1i\|2w1i]], [[2xa4\|2xa4]], [[4aqc\|4aqc]], [[4bbe\|4bbe]]</td></tr>
Line 29:		Line 29:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	~~[[Category: Human]]~~
	[[Category: Non-specific protein-tyrosine kinase]]		[[Category: Non-specific protein-tyrosine kinase]]
	[[Category: Li, J]]		[[Category: Li, J]]
	[[Category: Inhibitor]]		[[Category: Inhibitor]]
	[[Category: Transferase]]		[[Category: Transferase]]

OCA at 21:46, 5 August 2016

2016-08-05T21:46:34Z

← Older revision		Revision as of 21:46, 5 August 2016
Line 1:		Line 1:

	==Aminoalkylpyrimidine Inhibitor Complexes with JAK2==		==Aminoalkylpyrimidine Inhibitor Complexes with JAK2==
	<StructureSection load='4bbf' size='340' side='right' caption='[[4bbf]], [[Resolution\|resolution]] 2.00Å' scene=''>		<StructureSection load='4bbf' size='340' side='right' caption='[[4bbf]], [[Resolution\|resolution]] 2.00Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4bbf]] is a 4 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=4BBF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BBF FirstGlance]. <br>		<table><tr><td colspan='2'>[[4bbf]] is a 4 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=4BBF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BBF FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=O19:(2R)-N-[4-[2-[(4-MORPHOLIN-4-YLPHENYL)AMINO]PYRIMIDIN-4-YL]PHENYL]PYRROLIDINE-2-CARBOXAMIDE'>O19</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=O19:(2R)-N-[4-[2-[(4-MORPHOLIN-4-YLPHENYL)AMINO]PYRIMIDIN-4-YL]PHENYL]PYRROLIDINE-2-CARBOXAMIDE'>O19</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2b7a\|2b7a]], [[2w1i\|2w1i]], [[2xa4\|2xa4]], [[4aqc\|4aqc]], [[4bbe\|4bbe]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2b7a\|2b7a]], [[2w1i\|2w1i]], [[2xa4\|2xa4]], [[4aqc\|4aqc]], [[4bbe\|4bbe]]</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=4bbf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bbf OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4bbf RCSB], [http://www.ebi.ac.uk/pdbsum/4bbf 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=4bbf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bbf OCA], [http://pdbe.org/4bbf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4bbf RCSB], [http://www.ebi.ac.uk/pdbsum/4bbf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4bbf ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 20:		Line 21:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
			<div class="pdbe-citations 4bbf" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
Line 27:		Line 29:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: ~~Homo sapiens~~]]		[[Category: Human]]
	[[Category: Non-specific protein-tyrosine kinase]]		[[Category: Non-specific protein-tyrosine kinase]]
	[[Category: Li, J]]		[[Category: Li, J]]
	[[Category: Inhibitor]]		[[Category: Inhibitor]]
	[[Category: Transferase]]		[[Category: Transferase]]

OCA at 09:45, 21 December 2014

2014-12-21T09:45:09Z

← Older revision		Revision as of 09:45, 21 December 2014
Line 1:		Line 1:
	~~{{STRUCTURE_4bbf~~\| ~~PDB~~=4bbf \| ~~SCENE=~~ }}		==Aminoalkylpyrimidine Inhibitor Complexes with JAK2==
	===~~Aminoalkylpyrimidine Inhibitor Complexes~~ with JAK2===		<StructureSection load='4bbf' size='340' side='right' caption='[[4bbf]], [[Resolution\|resolution]] 2.00Å' scene=''>
	~~{{ABSTRACT_PUBMED_23127890}}~~		== Structural highlights ==
			<table><tr><td colspan='2'>[[4bbf]] is a 4 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=4BBF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BBF FirstGlance]. <br>
			</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=O19:(2R)-N-[4-[2-[(4-MORPHOLIN-4-YLPHENYL)AMINO]PYRIMIDIN-4-YL]PHENYL]PYRROLIDINE-2-CARBOXAMIDE'>O19</scene></td></tr>
			<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2b7a\|2b7a]], [[2w1i\|2w1i]], [[2xa4\|2xa4]], [[4aqc\|4aqc]], [[4bbe\|4bbe]]</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=4bbf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bbf OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4bbf RCSB], [http://www.ebi.ac.uk/pdbsum/4bbf 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 the discovery of a series of 4-aryl-2-aminoalkylpyrimidine derivatives as potent and selective JAK2 inhibitors. High throughput screening of our in-house compound library led to the identification of hit 1, from which optimization resulted in the discovery of highly potent and selective JAK2 inhibitors. Advanced lead 10d demonstrated a significant dose-dependent pharmacodynamic and antitumor effect in a mouse xenograft model. Based upon the desirable profile of 10d (XL019) it was advanced into clinical trials.

	~~==Disease==~~		SAR and in vivo evaluation of 4-aryl-2-aminoalkylpyrimidines as potent and selective Janus kinase 2 (JAK2) inhibitors.,Forsyth T, Kearney PC, Kim BG, Johnson HW, Aay N, Arcalas A, Brown DS, Chan V, Chen J, Du H, Epshteyn S, Galan AA, Huynh TP, Ibrahim MA, Kane B, Koltun ES, Mann G, Meyr LE, Lee MS, Lewis GL, Noguchi RT, Pack M, Ridgway BH, Shi X, Takeuchi CS, Zu P, Leahy JW, Nuss JM, Aoyama R, Engst S, Gendreau SB, Kassees R, Li J, Lin SH, Martini JF, Stout T, Tong P, Woolfrey J, Zhang W, Yu P Bioorg Med Chem Lett. 2012 Oct 16. pii: S0960-894X(12)01274-7. doi:, 10.1016/j.bmcl.2012.10.007. PMID:23127890<ref>PMID:23127890</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==
	[[~~4bbf~~]] is a 4 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=4BBF OCA].		*[[Janus kinase\|Janus kinase]]
			== References ==
	==~~Reference~~==		<references/>
	<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: Li, J.]]		[[Category: Li, J]]
	[[Category: Inhibitor]]		[[Category: Inhibitor]]
	[[Category: Transferase]]		[[Category: Transferase]]

OCA at 06:00, 25 March 2013

2013-03-25T06:00:24Z

← Older revision		Revision as of 06:00, 25 March 2013
Line 1:		Line 1:
	~~[[Image:4bbf.png\|left\|200px]]~~

	{{STRUCTURE_4bbf\| PDB=4bbf \| SCENE= }}		{{STRUCTURE_4bbf\| PDB=4bbf \| SCENE= }}
			===Aminoalkylpyrimidine Inhibitor Complexes with JAK2===
			{{ABSTRACT_PUBMED_23127890}}

	===~~Aminoalkylpyrimidine Inhibitor Complexes~~ with JAK2~~===~~		==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_23127890}}~~		==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==
	[[4bbf]] is a 4 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=4BBF OCA].		[[4bbf]] is a 4 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=4BBF OCA].

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

OCA at 10:35, 19 December 2012

2012-12-19T10:35:16Z

← Older revision		Revision as of 10:35, 19 December 2012
Line 1:		Line 1:
	[[Image:4bbf.~~jpg~~\|left\|200px]]		[[Image:4bbf.png\|left\|200px]]

	{{STRUCTURE_4bbf\| PDB=4bbf \| SCENE= }}		{{STRUCTURE_4bbf\| PDB=4bbf \| SCENE= }}

OCA at 09:34, 21 November 2012

2012-11-21T09:34:44Z

← Older revision		Revision as of 09:34, 21 November 2012
Line 1:		Line 1:
	~~'''Unreleased structure'''~~		[[Image:4bbf.jpg\|left\|200px]]

	~~The entry~~ 4bbf ~~is ON HOLD~~ ~~until Paper Publication~~		{{STRUCTURE_4bbf\| PDB=4bbf \| SCENE= }}

	~~Authors: Li, J.~~		===Aminoalkylpyrimidine Inhibitor Complexes with JAK2===

	~~Description~~: ~~Aminoalkylpyrimidine~~ Inhibitor ~~Complexes with JAK2~~		{{ABSTRACT_PUBMED_23127890}}

			==About this Structure==
			[[4bbf]] is a 4 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=4BBF OCA].
			[[Category: Homo sapiens]]
			[[Category: Non-specific protein-tyrosine kinase]]
			[[Category: Li, J.]]
			[[Category: Inhibitor]]
			[[Category: Transferase]]