5wim - Revision history

OCA at 14:16, 13 March 2024

2024-03-13T14:16:03Z

←Older revision		Revision as of 14:16, 13 March 2024
Line 3:		Line 3:
	<StructureSection load='5wim' size='340' side='right'caption='[[5wim]], [[Resolution\|resolution]] 2.55Å' scene=''>		<StructureSection load='5wim' size='340' side='right'caption='[[5wim]], [[Resolution\|resolution]] 2.55Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5wim]] is a 1 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WIM OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5WIM FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5wim]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WIM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5WIM FirstGlance]. <br>
-	</td></tr><tr id='~~ligand~~'><td class="sblockLbl"><b>[[~~Ligand~~\|~~Ligands~~:]]</b></td><td class="sblockDat">~~<scene name='pdbligand=35R:1-CYCLOPROPYL-3-{3~~-[~~5-(MORPHOLIN-4-YLMETHYL)-1H-BENZIMIDAZOL-~~2~~-YL]-1H-PYRAZOL-4-YL}UREA'>35R</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]] 2.55Å</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='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=35R:1-CYCLOPROPYL-3-{3-[5-(MORPHOLIN-4-YLMETHYL)-1H-BENZIMIDAZOL-2-YL]-1H-PYRAZOL-4-YL}UREA'>35R</scene></td></tr>
-	~~<tr id='activity'><td class~~="~~sblockLbl~~"><~~b>Activity:</b></td><td class~~=~~"sblockDat"><span class~~=~~'plainlinks'>[http~~:~~//en.wikipedia.org/wiki/Non~~-~~specific_protein~~-~~tyrosine_kinase Non~~-~~specific protein~~-~~tyrosine kinase], with EC number~~ [~~http://www.brenda~~-~~enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.~~2] </~~span~~></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5wim FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wim OCA], [https://pdbe.org/5wim PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5wim RCSB], [https://www.ebi.ac.uk/pdbsum/5wim PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5wim ProSAT]</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=5wim FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wim OCA], [~~http~~://pdbe.org/5wim PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5wim RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5wim PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5wim 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;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	The oncogenic V617F mutation lies in the pseudokinase domain of JAK2, marking it as a potential target for development of compounds that might inhibit the pathogenic activity of the mutant protein. We used differential scanning fluorimetry to identify compounds that bind the JAK2 pseudokinase domain. Crystal structures of five candidate compounds with the wild-type domain reveal their modes of binding. Exploration of analogs of screening hit BI-D1870 led to the identification of compound 2, a 123 nM ligand for the pseudokinase domain. Interestingly, crystal structures of the V617F domain in complex with two unrelated compounds reveal a conformation that is characteristic of the wild-type domain, rather than that previously observed for the V617F mutant. These structures suggest that certain ATP-site ligands can modulate the V617F allosteric site, thereby providing a mechanistic rationale for targeting the pseudokinase domain and a structural foundation for development of more potent and pseudokinase-selective compounds.	+

-	Discovery and Structural Characterization of ATP-Site Ligands for the Wild-Type and V617F Mutant JAK2 Pseudokinase Domain.,McNally R, Li Q, Li K, Dekker C, Vangrevelinghe E, Jones M, Chene P, Machauer R, Radimerski T, Eck MJ ACS Chem Biol. 2019 Mar 11. doi: 10.1021/acschembio.8b00722. PMID:30763067<ref>PMID:30763067</ref>	+	==See Also==
-		+	*[[Janus kinase 3D structures\|Janus kinase 3D structures]]
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class~~=~~"pdbe-citations 5wim" style~~=~~"background-color:#fffaf0;"></div>~~	+
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Non-specific protein-tyrosine kinase]]~~	+	[[Category: Eck MJ]]
-	[[Category: Eck~~, M J~~]]	+	[[Category: Li K]]
-	[[Category: Li, K]]	+	[[Category: Li Q]]
-	[[Category: Li, Q]]	+	[[Category: Park E]]
-	[[Category: Park, E]]	+
-	~~[[Category: At9283]]~~	+
-	~~[[Category: Jak2]]~~	+
-	~~[[Category: Pseudokinase]]~~	+
-	~~[[Category: Transferase~~]]	+

OCA at 08:16, 20 March 2019

2019-03-20T08:16:22Z

←Older revision		Revision as of 08:16, 20 March 2019
Line 1:		Line 1:

	==JAK2 Pseudokinase in complex with AT9283==		==JAK2 Pseudokinase in complex with AT9283==
-	<StructureSection load='5wim' size='340' side='right' caption='[[5wim]], [[Resolution\|resolution]] 2.55Å' scene=''>	+	<StructureSection load='5wim' size='340' side='right'caption='[[5wim]], [[Resolution\|resolution]] 2.55Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5wim]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WIM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5WIM FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5wim]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WIM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5WIM FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=35R:1-CYCLOPROPYL-3-{3-[5-(MORPHOLIN-4-YLMETHYL)-1H-BENZIMIDAZOL-2-YL]-1H-PYRAZOL-4-YL}UREA'>35R</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=35R:1-CYCLOPROPYL-3-{3-[5-(MORPHOLIN-4-YLMETHYL)-1H-BENZIMIDAZOL-2-YL]-1H-PYRAZOL-4-YL}UREA'>35R</scene></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=5wim FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wim OCA], [http://pdbe.org/5wim PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5wim RCSB], [http://www.ebi.ac.uk/pdbsum/5wim PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5wim ProSAT]</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=5wim FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wim OCA], [http://pdbe.org/5wim PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5wim RCSB], [http://www.ebi.ac.uk/pdbsum/5wim PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5wim ProSAT]</span></td></tr>
Line 12:		Line 13:
	== 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>		[[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 ==
		+	The oncogenic V617F mutation lies in the pseudokinase domain of JAK2, marking it as a potential target for development of compounds that might inhibit the pathogenic activity of the mutant protein. We used differential scanning fluorimetry to identify compounds that bind the JAK2 pseudokinase domain. Crystal structures of five candidate compounds with the wild-type domain reveal their modes of binding. Exploration of analogs of screening hit BI-D1870 led to the identification of compound 2, a 123 nM ligand for the pseudokinase domain. Interestingly, crystal structures of the V617F domain in complex with two unrelated compounds reveal a conformation that is characteristic of the wild-type domain, rather than that previously observed for the V617F mutant. These structures suggest that certain ATP-site ligands can modulate the V617F allosteric site, thereby providing a mechanistic rationale for targeting the pseudokinase domain and a structural foundation for development of more potent and pseudokinase-selective compounds.
		+
		+	Discovery and Structural Characterization of ATP-Site Ligands for the Wild-Type and V617F Mutant JAK2 Pseudokinase Domain.,McNally R, Li Q, Li K, Dekker C, Vangrevelinghe E, Jones M, Chene P, Machauer R, Radimerski T, Eck MJ ACS Chem Biol. 2019 Mar 11. doi: 10.1021/acschembio.8b00722. PMID:30763067<ref>PMID:30763067</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 5wim" style="background-color:#fffaf0;"></div>
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Non-specific protein-tyrosine kinase]]		[[Category: Non-specific protein-tyrosine kinase]]
	[[Category: Eck, M J]]		[[Category: Eck, M J]]

OCA at 18:36, 1 August 2018

2018-08-01T18:36:15Z

←Older revision		Revision as of 18:36, 1 August 2018
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 5wim is ~~ON HOLD until Paper Publication~~	+	==JAK2 Pseudokinase in complex with AT9283==
-		+	<StructureSection load='5wim' size='340' side='right' caption='[[5wim]], [[Resolution\|resolution]] 2.55Å' scene=''>
-	~~Authors~~: Li, Q., ~~Eck~~, M.J., Li, K., ~~Park~~, E.	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>[[5wim]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WIM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5WIM FirstGlance]. <br>
-	~~Description~~: JAK2 ~~Pseudokinase~~ in ~~complex~~ with ~~AT9283~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=35R:1-CYCLOPROPYL-3-{3-[5-(MORPHOLIN-4-YLMETHYL)-1H-BENZIMIDAZOL-2-YL]-1H-PYRAZOL-4-YL}UREA'>35R</scene></td></tr>
-	[[Category: ~~Unreleased Structures~~]]	+	<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=5wim FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wim OCA], [http://pdbe.org/5wim PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5wim RCSB], [http://www.ebi.ac.uk/pdbsum/5wim PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5wim ProSAT]</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>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Non-specific protein-tyrosine kinase]]
		+	[[Category: Eck, M J]]
	[[Category: Li, K]]		[[Category: Li, K]]
-	[[Category: Eck, M.J]]
	[[Category: Li, Q]]		[[Category: Li, Q]]
	[[Category: Park, E]]		[[Category: Park, E]]
		+	[[Category: At9283]]
		+	[[Category: Jak2]]
		+	[[Category: Pseudokinase]]
		+	[[Category: Transferase]]

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

2017-09-27T14:51:41Z

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

←Older revision

Revision as of 14:51, 27 September 2017

OCA: New page: '''Unreleased structure''' The entry 5wim is ON HOLD until Paper Publication Authors: Li, Q., Eck, M.J., Li, K., Park, E. Description: JAK2 Pseudokinase in complex with AT9283 [[Catego...

2017-09-27T14:51:40Z

New page: '''Unreleased structure''' The entry 5wim is ON HOLD until Paper Publication Authors: Li, Q., Eck, M.J., Li, K., Park, E. Description: JAK2 Pseudokinase in complex with AT9283 [[Catego...

New page

'''Unreleased structure'''

The entry 5wim is ON HOLD until Paper Publication

Authors: Li, Q., Eck, M.J., Li, K., Park, E.

Description: JAK2 Pseudokinase in complex with AT9283
[[Category: Unreleased Structures]]
[[Category: Li, K]]
[[Category: Eck, M.J]]
[[Category: Li, Q]]
[[Category: Park, E]]