7apg - Revision history

OCA at 12:13, 1 February 2024

OCA — Thu, 01 Feb 2024 12:13:33 GMT

←Older revision		Revision as of 12:13, 1 February 2024
Line 3:		Line 3:
	<StructureSection load='7apg' size='340' side='right'caption='[[7apg]], [[Resolution\|resolution]] 2.40Å' scene=''>		<StructureSection load='7apg' size='340' side='right'caption='[[7apg]], [[Resolution\|resolution]] 2.40Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[7apg]] 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=7APG OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=7APG FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7apg]] 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=7APG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7APG FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PHU:1-PHENYLUREA'>PHU</scene>, <scene name='pdbligand=RQT:~{N}-[3-(1~{H}-pyrrolo[2,3-b]pyridin-3-yl)phenyl]propanamide'>RQT</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]] 2.4Å</td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">JAK3 ([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=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PHU:1-PHENYLUREA'>PHU</scene>, <scene name='pdbligand=RQT:~{N}-[3-(1~{H}-pyrrolo[2,3-b]pyridin-3-yl)phenyl]propanamide'>RQT</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=7apg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7apg OCA], [https://pdbe.org/7apg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7apg RCSB], [https://www.ebi.ac.uk/pdbsum/7apg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7apg ProSAT]</span></td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://proteopedia.org/fgij/fg.htm?mol=7apg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7apg OCA], [~~http~~://pdbe.org/7apg PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=7apg RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/7apg PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=7apg ProSAT]</span></td></tr>	+
	</table>		</table>
	== Disease ==		== Disease ==
-	[~~[http~~://www.uniprot.org/uniprot/JAK3_HUMAN JAK3_HUMAN]] Defects in JAK3 are a cause of severe combined immunodeficiency autosomal recessive T-cell-negative/B-cell-positive/NK-cell-negative (T(-)B(+)NK(-) SCID) [MIM:[~~http~~://omim.org/entry/600802 600802]]. A form of severe combined immunodeficiency (SCID), a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients present in infancy recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development.<ref>PMID:15121872</ref> <ref>PMID:18250158</ref> <ref>PMID:15831699</ref> [:]<ref>PMID:7659163</ref> <ref>PMID:9354668</ref> <ref>PMID:9753072</ref> <ref>PMID:10982185</ref> <ref>PMID:14615376</ref>	+	[https://www.uniprot.org/uniprot/JAK3_HUMAN JAK3_HUMAN] Defects in JAK3 are a cause of severe combined immunodeficiency autosomal recessive T-cell-negative/B-cell-positive/NK-cell-negative (T(-)B(+)NK(-) SCID) [MIM:[https://omim.org/entry/600802 600802]. A form of severe combined immunodeficiency (SCID), a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients present in infancy recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development.<ref>PMID:15121872</ref> <ref>PMID:18250158</ref> <ref>PMID:15831699</ref> [:]<ref>PMID:7659163</ref> <ref>PMID:9354668</ref> <ref>PMID:9753072</ref> <ref>PMID:10982185</ref> <ref>PMID:14615376</ref>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/JAK3_HUMAN JAK3_HUMAN]] Non-receptor tyrosine kinase involved in various processes such as cell growth, development, or differentiation. Mediates essential signaling events in both innate and adaptive immunity and plays a crucial role in hematopoiesis during T-cells development. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors sharing the common subunit gamma such as IL2R, IL4R, IL7R, IL9R, IL15R and IL21R. 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, upon IL2R activation by IL2, JAK1 and JAK3 molecules bind to IL2R beta (IL2RB) and gamma chain (IL2RG) subunits inducing the tyrosine phosphorylation of both receptor subunits on their cytoplasmic domain. Then, STAT5A AND STAT5B are recruited, phosphorylated and activated by JAK1 and JAK3. Once activated, dimerized STAT5 translocates to the nucleus and promotes the transcription of specific target genes in a cytokine-specific fashion.<ref>PMID:8022485</ref> <ref>PMID:7662955</ref> <ref>PMID:20440074</ref>	+	[https://www.uniprot.org/uniprot/JAK3_HUMAN JAK3_HUMAN] Non-receptor tyrosine kinase involved in various processes such as cell growth, development, or differentiation. Mediates essential signaling events in both innate and adaptive immunity and plays a crucial role in hematopoiesis during T-cells development. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors sharing the common subunit gamma such as IL2R, IL4R, IL7R, IL9R, IL15R and IL21R. 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, upon IL2R activation by IL2, JAK1 and JAK3 molecules bind to IL2R beta (IL2RB) and gamma chain (IL2RG) subunits inducing the tyrosine phosphorylation of both receptor subunits on their cytoplasmic domain. Then, STAT5A AND STAT5B are recruited, phosphorylated and activated by JAK1 and JAK3. Once activated, dimerized STAT5 translocates to the nucleus and promotes the transcription of specific target genes in a cytokine-specific fashion.<ref>PMID:8022485</ref> <ref>PMID:7662955</ref> <ref>PMID:20440074</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 22:		Line 21:
	</div>		</div>
	<div class="pdbe-citations 7apg" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 7apg" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Janus kinase 3D structures\|Janus kinase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Non-specific protein-tyrosine kinase]]~~	+	[[Category: Chaikuad A]]
-	[[Category: Chaikuad, A]]	+	[[Category: Forster M]]
-	[[Category: Forster, M]]	+	[[Category: Gehringer M]]
-	[[Category: Gehringer, M]]	+	[[Category: Knapp S]]
-	[[Category: Knapp, S]]	+	[[Category: Laufer S]]
-	[[Category: Laufer, S]]	+
-	~~[[Category: Structural genomic]]~~	+
-	~~[[Category: Covalent inhibitor]]~~	+
-	~~[[Category: Inhibitor]]~~	+
-	~~[[Category: Jak3]]~~	+
-	~~[[Category: Kinase]]~~	+
-	~~[[Category: Sgc]]~~	+
-	~~[[Category: Transferase~~]]	+

OCA at 06:03, 20 January 2021

OCA — Wed, 20 Jan 2021 06:03:58 GMT

←Older revision		Revision as of 06:03, 20 January 2021
Line 1:		Line 1:

	==Crystal structure of JAK3 in complex with FM587 (compound 9a)==		==Crystal structure of JAK3 in complex with FM587 (compound 9a)==
-	<StructureSection load='7apg' size='340' side='right'caption='[[7apg]]' scene=''>	+	<StructureSection load='7apg' size='340' side='right'caption='[[7apg]], [[Resolution\|resolution]] 2.40Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7APG OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=7APG FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7apg]] 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=7APG OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=7APG FirstGlance]. <br>
-	</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=7apg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7apg OCA], [http://pdbe.org/7apg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=7apg RCSB], [http://www.ebi.ac.uk/pdbsum/7apg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=7apg ProSAT]</span></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PHU:1-PHENYLUREA'>PHU</scene>, <scene name='pdbligand=RQT:~{N}-[3-(1~{H}-pyrrolo[2,3-b]pyridin-3-yl)phenyl]propanamide'>RQT</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">JAK3 ([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://proteopedia.org/fgij/fg.htm?mol=7apg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7apg OCA], [http://pdbe.org/7apg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=7apg RCSB], [http://www.ebi.ac.uk/pdbsum/7apg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=7apg ProSAT]</span></td></tr>
	</table>		</table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/JAK3_HUMAN JAK3_HUMAN]] Defects in JAK3 are a cause of severe combined immunodeficiency autosomal recessive T-cell-negative/B-cell-positive/NK-cell-negative (T(-)B(+)NK(-) SCID) [MIM:[http://omim.org/entry/600802 600802]]. A form of severe combined immunodeficiency (SCID), a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients present in infancy recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development.<ref>PMID:15121872</ref> <ref>PMID:18250158</ref> <ref>PMID:15831699</ref> [:]<ref>PMID:7659163</ref> <ref>PMID:9354668</ref> <ref>PMID:9753072</ref> <ref>PMID:10982185</ref> <ref>PMID:14615376</ref>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/JAK3_HUMAN JAK3_HUMAN]] Non-receptor tyrosine kinase involved in various processes such as cell growth, development, or differentiation. Mediates essential signaling events in both innate and adaptive immunity and plays a crucial role in hematopoiesis during T-cells development. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors sharing the common subunit gamma such as IL2R, IL4R, IL7R, IL9R, IL15R and IL21R. 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, upon IL2R activation by IL2, JAK1 and JAK3 molecules bind to IL2R beta (IL2RB) and gamma chain (IL2RG) subunits inducing the tyrosine phosphorylation of both receptor subunits on their cytoplasmic domain. Then, STAT5A AND STAT5B are recruited, phosphorylated and activated by JAK1 and JAK3. Once activated, dimerized STAT5 translocates to the nucleus and promotes the transcription of specific target genes in a cytokine-specific fashion.<ref>PMID:8022485</ref> <ref>PMID:7662955</ref> <ref>PMID:20440074</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The nonreceptor tyrosine TEC kinases are key regulators of the immune system and play a crucial role in the pathogenesis of diverse hematological malignancies. In contrast to the substantial efforts in inhibitor development for Bruton's tyrosine kinase (BTK), specific inhibitors of the other TEC kinases, including the bone marrow tyrosine kinase on chromosome X (BMX), remain sparse. Here we present a novel class of dual BMX/BTK inhibitors, which were designed from irreversible inhibitors of Janus kinase (JAK) 3 targeting a cysteine located within the solvent-exposed front region of the ATP binding pocket. Structure-guided design exploiting the differences in the gatekeeper residues enabled the achievement of high selectivity over JAK3 and certain other kinases harboring a sterically demanding residue at this position. The most active compounds inhibited BMX and BTK with apparent IC50 values in the single digit nanomolar range or below showing moderate selectivity within the TEC family and potent cellular target engagement. These compounds represent an important first step towards selective chemical probes for the protein kinase BMX.
		+
		+	Discovery of a Novel Class of Covalent Dual Inhibitors Targeting the Protein Kinases BMX and BTK.,Forster M, Liang XJ, Schroder M, Gerstenecker S, Chaikuad A, Knapp S, Laufer S, Gehringer M Int J Mol Sci. 2020 Dec 4;21(23). pii: ijms21239269. doi: 10.3390/ijms21239269. PMID:33291717<ref>PMID:33291717</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7apg" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Chaikuad A]]	+	[[Category: Non-specific protein-tyrosine kinase]]
-	[[Category: Forster M]]	+	[[Category: Chaikuad, A]]
-	[[Category: Gehringer M]]	+	[[Category: Forster, M]]
-	[[Category: Knapp S]]	+	[[Category: Gehringer, M]]
-	[[Category: Laufer S]]	+	[[Category: Knapp, S]]
		+	[[Category: Laufer, S]]
		+	[[Category: Structural genomic]]
		+	[[Category: Covalent inhibitor]]
		+	[[Category: Inhibitor]]
		+	[[Category: Jak3]]
		+	[[Category: Kinase]]
		+	[[Category: Sgc]]
		+	[[Category: Transferase]]

OCA at 07:51, 2 December 2020

OCA — Wed, 02 Dec 2020 07:51:10 GMT

←Older revision		Revision as of 07:51, 2 December 2020
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 7apg ~~is ON HOLD~~	+	==Crystal structure of JAK3 in complex with FM587 (compound 9a)==
-		+	<StructureSection load='7apg' size='340' side='right'caption='[[7apg]]' scene=''>
-	~~Authors~~: ~~Chaikuad, A~~., ~~Forster, M~~., ~~Gehringer, M~~., ~~Laufer, S~~., ~~Knapp, S~~., ~~Structural Genomics Consortium (SGC)~~	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7APG OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=7APG FirstGlance]. <br>
-	~~Description: Crystal structure of JAK3 in complex with FM587 (compound 9a)~~	+	</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=7apg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7apg OCA], [http://pdbe.org/7apg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=7apg RCSB], [http://www.ebi.ac.uk/pdbsum/7apg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=7apg ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
-	[[Category: Chaikuad, A]]	+	__TOC__
-	[[Category: ~~Gehringer,~~ M]]	+	</StructureSection>
-	[[Category: ~~Forster,~~ M]]	+	[[Category: Large Structures]]
-	[[Category: Knapp, S]]	+	[[Category: Chaikuad A]]
-	[[Category: Laufer, S]]	+	[[Category: Forster M]]
-	~~[[Category: Structural Genomics Consortium (Sgc)~~]]	+	[[Category: Gehringer M]]
		+	[[Category: Knapp S]]
		+	[[Category: Laufer S]]

OCA: Protected "7apg" [edit=sysop:move=sysop]

OCA — Wed, 28 Oct 2020 18:56:01 GMT

Protected "7apg" [edit=sysop:move=sysop]

←Older revision

Revision as of 18:56, 28 October 2020

OCA: New page: '''Unreleased structure''' The entry 7apg is ON HOLD Authors: Chaikuad, A., Forster, M., Gehringer, M., Laufer, S., Knapp, S., Structural Genomics Consortium (SGC) Description: Crystal...

OCA — Wed, 28 Oct 2020 18:56:00 GMT

New page: '''Unreleased structure''' The entry 7apg is ON HOLD Authors: Chaikuad, A., Forster, M., Gehringer, M., Laufer, S., Knapp, S., Structural Genomics Consortium (SGC) Description: Crystal...

New page

'''Unreleased structure'''

The entry 7apg is ON HOLD

Authors: Chaikuad, A., Forster, M., Gehringer, M., Laufer, S., Knapp, S., Structural Genomics Consortium (SGC)

Description: Crystal structure of JAK3 in complex with FM587 (compound 9a)
[[Category: Unreleased Structures]]
[[Category: Chaikuad, A]]
[[Category: Gehringer, M]]
[[Category: Forster, M]]
[[Category: Knapp, S]]
[[Category: Laufer, S]]
[[Category: Structural Genomics Consortium (Sgc)]]