5cxz - Revision history

OCA at 12:22, 6 March 2024

2024-03-06T12:22:20Z

←Older revision		Revision as of 12:22, 6 March 2024
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[5cxz]] 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=5CXZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5CXZ FirstGlance]. <br>		<table><tr><td colspan='2'>[[5cxz]] 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=5CXZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5CXZ FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=55U:N-{7-[4-(DIMETHYLAMINO)PHENYL]-1,6-NAPHTHYRIDIN-5-YL}PROPANE-1,3-DIAMINE'>55U</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 1.7Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=55U:N-{7-[4-(DIMETHYLAMINO)PHENYL]-1,6-NAPHTHYRIDIN-5-YL}PROPANE-1,3-DIAMINE'>55U</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5cxz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cxz OCA], [https://pdbe.org/5cxz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5cxz RCSB], [https://www.ebi.ac.uk/pdbsum/5cxz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5cxz 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=5cxz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cxz OCA], [https://pdbe.org/5cxz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5cxz RCSB], [https://www.ebi.ac.uk/pdbsum/5cxz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5cxz ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/KSYK_HUMAN KSYK_HUMAN] Non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immunoreceptors like the B-cell receptor (BCR). Regulates several biological processes including innate and adaptive immunity, cell adhesion, osteoclast maturation, platelet activation and vascular development. Assembles into signaling complexes with activated receptors at the plasma membrane via interaction between its SH2 domains and the receptor tyrosine-phosphorylated ITAM domains. The association with the receptor can also be indirect and mediated by adapter proteins containing ITAM or partial hemITAM domains. The phosphorylation of the ITAM domains is generally mediated by SRC subfamily kinases upon engagement of the receptor. More rarely signal transduction via SYK could be ITAM-independent. Direct downstream effectors phosphorylated by SYK include VAV1, PLCG1, PI-3-kinase, LCP2 and BLNK. Initially identified as essential in B-cell receptor (BCR) signaling, it is necessary for the maturation of B-cells most probably at the pro-B to pre-B transition. Activated upon BCR engagement, it phosphorylates and activates BLNK an adapter linking the activated BCR to downstream signaling adapters and effectors. It also phosphorylates and activates PLCG1 and the PKC signaling pathway. It also phosphorylates BTK and regulates its activity in B-cell antigen receptor (BCR)-coupled signaling. Beside its function downstream of BCR plays also a role in T-cell receptor signaling. Plays also a crucial role in the innate immune response to fungal, bacterial and viral pathogens. It is for instance activated by the membrane lectin CLEC7A. Upon stimulation by fungal proteins, CLEC7A together with SYK activates immune cells inducing the production of ROS. Also activates the inflammasome and NF-kappa-B-mediated transcription of chemokines and cytokines in presence of pathogens. Regulates neutrophil degranulation and phagocytosis through activation of the MAPK signaling cascade. Also mediates the activation of dendritic cells by cell necrosis stimuli. Also involved in mast cells activation. Also functions downstream of receptors mediating cell adhesion. Relays for instance, integrin-mediated neutrophils and macrophages activation and P-selectin receptor/SELPG-mediated recruitment of leukocytes to inflammatory loci. Plays also a role in non-immune processes. It is for instance involved in vascular development where it may regulate blood and lymphatic vascular separation. It is also required for osteoclast development and function. Functions in the activation of platelets by collagen, mediating PLCG2 phosphorylation and activation. May be coupled to the collagen receptor by the ITAM domain-containing FCER1G. Also activated by the membrane lectin CLEC1B that is required for activation of platelets by PDPN/podoplanin. Involved in platelet adhesion being activated by ITGB3 engaged by fibrinogen.<ref>PMID:8657103</ref> <ref>PMID:9535867</ref> <ref>PMID:12456653</ref> <ref>PMID:12387735</ref> <ref>PMID:15388330</ref> <ref>PMID:19909739</ref>		[https://www.uniprot.org/uniprot/KSYK_HUMAN KSYK_HUMAN] Non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immunoreceptors like the B-cell receptor (BCR). Regulates several biological processes including innate and adaptive immunity, cell adhesion, osteoclast maturation, platelet activation and vascular development. Assembles into signaling complexes with activated receptors at the plasma membrane via interaction between its SH2 domains and the receptor tyrosine-phosphorylated ITAM domains. The association with the receptor can also be indirect and mediated by adapter proteins containing ITAM or partial hemITAM domains. The phosphorylation of the ITAM domains is generally mediated by SRC subfamily kinases upon engagement of the receptor. More rarely signal transduction via SYK could be ITAM-independent. Direct downstream effectors phosphorylated by SYK include VAV1, PLCG1, PI-3-kinase, LCP2 and BLNK. Initially identified as essential in B-cell receptor (BCR) signaling, it is necessary for the maturation of B-cells most probably at the pro-B to pre-B transition. Activated upon BCR engagement, it phosphorylates and activates BLNK an adapter linking the activated BCR to downstream signaling adapters and effectors. It also phosphorylates and activates PLCG1 and the PKC signaling pathway. It also phosphorylates BTK and regulates its activity in B-cell antigen receptor (BCR)-coupled signaling. Beside its function downstream of BCR plays also a role in T-cell receptor signaling. Plays also a crucial role in the innate immune response to fungal, bacterial and viral pathogens. It is for instance activated by the membrane lectin CLEC7A. Upon stimulation by fungal proteins, CLEC7A together with SYK activates immune cells inducing the production of ROS. Also activates the inflammasome and NF-kappa-B-mediated transcription of chemokines and cytokines in presence of pathogens. Regulates neutrophil degranulation and phagocytosis through activation of the MAPK signaling cascade. Also mediates the activation of dendritic cells by cell necrosis stimuli. Also involved in mast cells activation. Also functions downstream of receptors mediating cell adhesion. Relays for instance, integrin-mediated neutrophils and macrophages activation and P-selectin receptor/SELPG-mediated recruitment of leukocytes to inflammatory loci. Plays also a role in non-immune processes. It is for instance involved in vascular development where it may regulate blood and lymphatic vascular separation. It is also required for osteoclast development and function. Functions in the activation of platelets by collagen, mediating PLCG2 phosphorylation and activation. May be coupled to the collagen receptor by the ITAM domain-containing FCER1G. Also activated by the membrane lectin CLEC1B that is required for activation of platelets by PDPN/podoplanin. Involved in platelet adhesion being activated by ITGB3 engaged by fibrinogen.<ref>PMID:8657103</ref> <ref>PMID:9535867</ref> <ref>PMID:12456653</ref> <ref>PMID:12387735</ref> <ref>PMID:15388330</ref> <ref>PMID:19909739</ref>
-	<div style="background-color:#fffaf0;">
-	== Publication Abstract from PubMed ==
-	Design and optimization of benzo- and pyrido-thiazoles/isothiazoles are reported leading to the discovery of the potent, orally bioavailable Syk inhibitor 5, which was found to be active in a rat PK/PD model. Compound 5 showed acceptable overall kinase selectivity. However, in addition to Syk it also inhibited Aurora kinase in enzymatic and cellular settings leading to findings in the micronucleus assay. As a consequence, compound 5 was not further pursued.
-
-	Orally bioavailable Syk inhibitors with activity in a rat PK/PD model.,Thoma G, Veenstra S, Strang R, Blanz J, Vangrevelinghe E, Berghausen J, Lee CC, Zerwes HG Bioorg Med Chem Lett. 2015 Oct 15;25(20):4642-7. doi: 10.1016/j.bmcl.2015.08.037., Epub 2015 Aug 18. PMID:26320624<ref>PMID:26320624</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 5cxz" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==

OCA at 10:13, 21 June 2023

2023-06-21T10:13:30Z

←Older revision		Revision as of 10:13, 21 June 2023
Line 1:		Line 1:

	==SYK catalytic domain complexed with naphthyridine inhibitor==		==SYK catalytic domain complexed with naphthyridine inhibitor==
-	<StructureSection load='5cxz' size='340' side='right' caption='[[5cxz]], [[Resolution\|resolution]] 1.70Å' scene=''>	+	<StructureSection load='5cxz' size='340' side='right'caption='[[5cxz]], [[Resolution\|resolution]] 1.70Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5cxz]] 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=5CXZ OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5CXZ FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5cxz]] 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=5CXZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5CXZ FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=55U:N-{7-[4-(DIMETHYLAMINO)PHENYL]-1,6-NAPHTHYRIDIN-5-YL}PROPANE-1,3-DIAMINE'>55U</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene~~></td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=55U:N-{7-[4-(DIMETHYLAMINO)PHENYL]-1,6-NAPHTHYRIDIN-5-YL}PROPANE-1,3-DIAMINE'>55U</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">SYK ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=5cxz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cxz OCA], [https://pdbe.org/5cxz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5cxz RCSB], [https://www.ebi.ac.uk/pdbsum/5cxz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5cxz ProSAT]</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=5cxz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cxz OCA], [~~http~~://pdbe.org/5cxz PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5cxz RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5cxz PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5cxz ProSAT]</span></td></tr>	+
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/KSYK_HUMAN KSYK_HUMAN]] Non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immunoreceptors like the B-cell receptor (BCR). Regulates several biological processes including innate and adaptive immunity, cell adhesion, osteoclast maturation, platelet activation and vascular development. Assembles into signaling complexes with activated receptors at the plasma membrane via interaction between its SH2 domains and the receptor tyrosine-phosphorylated ITAM domains. The association with the receptor can also be indirect and mediated by adapter proteins containing ITAM or partial hemITAM domains. The phosphorylation of the ITAM domains is generally mediated by SRC subfamily kinases upon engagement of the receptor. More rarely signal transduction via SYK could be ITAM-independent. Direct downstream effectors phosphorylated by SYK include VAV1, PLCG1, PI-3-kinase, LCP2 and BLNK. Initially identified as essential in B-cell receptor (BCR) signaling, it is necessary for the maturation of B-cells most probably at the pro-B to pre-B transition. Activated upon BCR engagement, it phosphorylates and activates BLNK an adapter linking the activated BCR to downstream signaling adapters and effectors. It also phosphorylates and activates PLCG1 and the PKC signaling pathway. It also phosphorylates BTK and regulates its activity in B-cell antigen receptor (BCR)-coupled signaling. Beside its function downstream of BCR plays also a role in T-cell receptor signaling. Plays also a crucial role in the innate immune response to fungal, bacterial and viral pathogens. It is for instance activated by the membrane lectin CLEC7A. Upon stimulation by fungal proteins, CLEC7A together with SYK activates immune cells inducing the production of ROS. Also activates the inflammasome and NF-kappa-B-mediated transcription of chemokines and cytokines in presence of pathogens. Regulates neutrophil degranulation and phagocytosis through activation of the MAPK signaling cascade. Also mediates the activation of dendritic cells by cell necrosis stimuli. Also involved in mast cells activation. Also functions downstream of receptors mediating cell adhesion. Relays for instance, integrin-mediated neutrophils and macrophages activation and P-selectin receptor/SELPG-mediated recruitment of leukocytes to inflammatory loci. Plays also a role in non-immune processes. It is for instance involved in vascular development where it may regulate blood and lymphatic vascular separation. It is also required for osteoclast development and function. Functions in the activation of platelets by collagen, mediating PLCG2 phosphorylation and activation. May be coupled to the collagen receptor by the ITAM domain-containing FCER1G. Also activated by the membrane lectin CLEC1B that is required for activation of platelets by PDPN/podoplanin. Involved in platelet adhesion being activated by ITGB3 engaged by fibrinogen.<ref>PMID:8657103</ref> <ref>PMID:9535867</ref> <ref>PMID:12456653</ref> <ref>PMID:12387735</ref> <ref>PMID:15388330</ref> <ref>PMID:19909739</ref>	+	[https://www.uniprot.org/uniprot/KSYK_HUMAN KSYK_HUMAN] Non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immunoreceptors like the B-cell receptor (BCR). Regulates several biological processes including innate and adaptive immunity, cell adhesion, osteoclast maturation, platelet activation and vascular development. Assembles into signaling complexes with activated receptors at the plasma membrane via interaction between its SH2 domains and the receptor tyrosine-phosphorylated ITAM domains. The association with the receptor can also be indirect and mediated by adapter proteins containing ITAM or partial hemITAM domains. The phosphorylation of the ITAM domains is generally mediated by SRC subfamily kinases upon engagement of the receptor. More rarely signal transduction via SYK could be ITAM-independent. Direct downstream effectors phosphorylated by SYK include VAV1, PLCG1, PI-3-kinase, LCP2 and BLNK. Initially identified as essential in B-cell receptor (BCR) signaling, it is necessary for the maturation of B-cells most probably at the pro-B to pre-B transition. Activated upon BCR engagement, it phosphorylates and activates BLNK an adapter linking the activated BCR to downstream signaling adapters and effectors. It also phosphorylates and activates PLCG1 and the PKC signaling pathway. It also phosphorylates BTK and regulates its activity in B-cell antigen receptor (BCR)-coupled signaling. Beside its function downstream of BCR plays also a role in T-cell receptor signaling. Plays also a crucial role in the innate immune response to fungal, bacterial and viral pathogens. It is for instance activated by the membrane lectin CLEC7A. Upon stimulation by fungal proteins, CLEC7A together with SYK activates immune cells inducing the production of ROS. Also activates the inflammasome and NF-kappa-B-mediated transcription of chemokines and cytokines in presence of pathogens. Regulates neutrophil degranulation and phagocytosis through activation of the MAPK signaling cascade. Also mediates the activation of dendritic cells by cell necrosis stimuli. Also involved in mast cells activation. Also functions downstream of receptors mediating cell adhesion. Relays for instance, integrin-mediated neutrophils and macrophages activation and P-selectin receptor/SELPG-mediated recruitment of leukocytes to inflammatory loci. Plays also a role in non-immune processes. It is for instance involved in vascular development where it may regulate blood and lymphatic vascular separation. It is also required for osteoclast development and function. Functions in the activation of platelets by collagen, mediating PLCG2 phosphorylation and activation. May be coupled to the collagen receptor by the ITAM domain-containing FCER1G. Also activated by the membrane lectin CLEC1B that is required for activation of platelets by PDPN/podoplanin. Involved in platelet adhesion being activated by ITGB3 engaged by fibrinogen.<ref>PMID:8657103</ref> <ref>PMID:9535867</ref> <ref>PMID:12456653</ref> <ref>PMID:12387735</ref> <ref>PMID:15388330</ref> <ref>PMID:19909739</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 20:		Line 18:
	</div>		</div>
	<div class="pdbe-citations 5cxz" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 5cxz" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Tyrosine kinase 3D structures\|Tyrosine kinase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
-	[[Category: ~~Non-specific protein-tyrosine kinase~~]]	+	[[Category: Large Structures]]
-	[[Category: Berghausen, J]]	+	[[Category: Berghausen J]]
-	[[Category: Blanz, J]]	+	[[Category: Blanz J]]
-	[[Category: Lee~~, C C~~]]	+	[[Category: Lee CC]]
-	[[Category: Strang, R]]	+	[[Category: Strang R]]
-	[[Category: Thoma, G]]	+	[[Category: Thoma G]]
-	[[Category: Vangrevelinghe, E]]	+	[[Category: Vangrevelinghe E]]
-	[[Category: Veenstra, S]]	+	[[Category: Veenstra S]]
-	[[Category: Zerwes, H G]]	+	[[Category: Zerwes H-G]]
-	~~[[Category: Transferase-transferase inhibitor complex]]~~	+
-	~~[[Category: Transferase/transferase inhibitor~~]]	+

OCA at 17:18, 16 November 2017

2017-11-16T17:18:27Z

←Older revision		Revision as of 17:18, 16 November 2017
Line 1:		Line 1:
		+
	==SYK catalytic domain complexed with naphthyridine inhibitor==		==SYK catalytic domain complexed with naphthyridine inhibitor==
	<StructureSection load='5cxz' size='340' side='right' caption='[[5cxz]], [[Resolution\|resolution]] 1.70Å' scene=''>		<StructureSection load='5cxz' size='340' side='right' caption='[[5cxz]], [[Resolution\|resolution]] 1.70Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5cxz]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5CXZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5CXZ FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5cxz]] 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=5CXZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5CXZ FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=55U:N-{7-[4-(DIMETHYLAMINO)PHENYL]-1,6-NAPHTHYRIDIN-5-YL}PROPANE-1,3-DIAMINE'>55U</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=55U:N-{7-[4-(DIMETHYLAMINO)PHENYL]-1,6-NAPHTHYRIDIN-5-YL}PROPANE-1,3-DIAMINE'>55U</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">SYK ([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=5cxz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cxz OCA], [http://pdbe.org/5cxz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5cxz RCSB], [http://www.ebi.ac.uk/pdbsum/5cxz 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=5cxz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cxz OCA], [http://pdbe.org/5cxz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5cxz RCSB], [http://www.ebi.ac.uk/pdbsum/5cxz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5cxz ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 22:		Line 24:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Non-specific protein-tyrosine kinase]]		[[Category: Non-specific protein-tyrosine kinase]]
	[[Category: Berghausen, J]]		[[Category: Berghausen, J]]

OCA at 21:47, 15 October 2015

2015-10-15T21:47:20Z

←Older revision		Revision as of 21:47, 15 October 2015
Line 1:		Line 1:
-	'''~~Unreleased~~ structure'''	+	==SYK catalytic domain complexed with naphthyridine inhibitor==
		+	<StructureSection load='5cxz' size='340' side='right' caption='[[5cxz]], [[Resolution\|resolution]] 1.70Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5cxz]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5CXZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5CXZ FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=55U:N-{7-[4-(DIMETHYLAMINO)PHENYL]-1,6-NAPHTHYRIDIN-5-YL}PROPANE-1,3-DIAMINE'>55U</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5cxz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cxz OCA], [http://pdbe.org/5cxz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5cxz RCSB], [http://www.ebi.ac.uk/pdbsum/5cxz PDBsum]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/KSYK_HUMAN KSYK_HUMAN]] Non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immunoreceptors like the B-cell receptor (BCR). Regulates several biological processes including innate and adaptive immunity, cell adhesion, osteoclast maturation, platelet activation and vascular development. Assembles into signaling complexes with activated receptors at the plasma membrane via interaction between its SH2 domains and the receptor tyrosine-phosphorylated ITAM domains. The association with the receptor can also be indirect and mediated by adapter proteins containing ITAM or partial hemITAM domains. The phosphorylation of the ITAM domains is generally mediated by SRC subfamily kinases upon engagement of the receptor. More rarely signal transduction via SYK could be ITAM-independent. Direct downstream effectors phosphorylated by SYK include VAV1, PLCG1, PI-3-kinase, LCP2 and BLNK. Initially identified as essential in B-cell receptor (BCR) signaling, it is necessary for the maturation of B-cells most probably at the pro-B to pre-B transition. Activated upon BCR engagement, it phosphorylates and activates BLNK an adapter linking the activated BCR to downstream signaling adapters and effectors. It also phosphorylates and activates PLCG1 and the PKC signaling pathway. It also phosphorylates BTK and regulates its activity in B-cell antigen receptor (BCR)-coupled signaling. Beside its function downstream of BCR plays also a role in T-cell receptor signaling. Plays also a crucial role in the innate immune response to fungal, bacterial and viral pathogens. It is for instance activated by the membrane lectin CLEC7A. Upon stimulation by fungal proteins, CLEC7A together with SYK activates immune cells inducing the production of ROS. Also activates the inflammasome and NF-kappa-B-mediated transcription of chemokines and cytokines in presence of pathogens. Regulates neutrophil degranulation and phagocytosis through activation of the MAPK signaling cascade. Also mediates the activation of dendritic cells by cell necrosis stimuli. Also involved in mast cells activation. Also functions downstream of receptors mediating cell adhesion. Relays for instance, integrin-mediated neutrophils and macrophages activation and P-selectin receptor/SELPG-mediated recruitment of leukocytes to inflammatory loci. Plays also a role in non-immune processes. It is for instance involved in vascular development where it may regulate blood and lymphatic vascular separation. It is also required for osteoclast development and function. Functions in the activation of platelets by collagen, mediating PLCG2 phosphorylation and activation. May be coupled to the collagen receptor by the ITAM domain-containing FCER1G. Also activated by the membrane lectin CLEC1B that is required for activation of platelets by PDPN/podoplanin. Involved in platelet adhesion being activated by ITGB3 engaged by fibrinogen.<ref>PMID:8657103</ref> <ref>PMID:9535867</ref> <ref>PMID:12456653</ref> <ref>PMID:12387735</ref> <ref>PMID:15388330</ref> <ref>PMID:19909739</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Design and optimization of benzo- and pyrido-thiazoles/isothiazoles are reported leading to the discovery of the potent, orally bioavailable Syk inhibitor 5, which was found to be active in a rat PK/PD model. Compound 5 showed acceptable overall kinase selectivity. However, in addition to Syk it also inhibited Aurora kinase in enzymatic and cellular settings leading to findings in the micronucleus assay. As a consequence, compound 5 was not further pursued.

-	~~The entry 5cxz is ON HOLD until Paper Publication~~	+	Orally bioavailable Syk inhibitors with activity in a rat PK/PD model.,Thoma G, Veenstra S, Strang R, Blanz J, Vangrevelinghe E, Berghausen J, Lee CC, Zerwes HG Bioorg Med Chem Lett. 2015 Oct 15;25(20):4642-7. doi: 10.1016/j.bmcl.2015.08.037., Epub 2015 Aug 18. PMID:26320624<ref>PMID:26320624</ref>

-	~~Authors: Thoma~~, G.~~, Veenstra,~~ S.~~, Strang, R., Blanz, J., Vangrevelinghe, E., Berghausen, J., Lee, C.C., Zerwes, H.-G~~.	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-		+	</div>
-	~~Description~~: ~~SYK catalytic domain complexed with naphthyridine inhibitor~~	+	<div class="pdbe-citations 5cxz" style="background-color:#fffaf0;"></div>
-	[[Category: ~~Unreleased Structures~~]]	+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Non-specific protein-tyrosine kinase]]
	[[Category: Berghausen, J]]		[[Category: Berghausen, J]]
-	[[Category: Thoma, G]]
	[[Category: Blanz, J]]		[[Category: Blanz, J]]
		+	[[Category: Lee, C C]]
	[[Category: Strang, R]]		[[Category: Strang, R]]
-	[[Category: ~~Lee~~, ~~C.C~~]]	+	[[Category: Thoma, G]]
		+	[[Category: Vangrevelinghe, E]]
	[[Category: Veenstra, S]]		[[Category: Veenstra, S]]
-	[[Category: Zerwes, H.-G]]	+	[[Category: Zerwes, H G]]
-	[[Category: ~~Vangrevelinghe, E~~]]	+	[[Category: Transferase-transferase inhibitor complex]]
		+	[[Category: Transferase/transferase inhibitor]]

OCA at 13:34, 12 August 2015

2015-08-12T13:34:28Z

←Older revision		Revision as of 13:34, 12 August 2015
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 5cxz is ON HOLD	+	The entry 5cxz is ON HOLD until Paper Publication

	Authors: Thoma, G., Veenstra, S., Strang, R., Blanz, J., Vangrevelinghe, E., Berghausen, J., Lee, C.C., Zerwes, H.-G.		Authors: Thoma, G., Veenstra, S., Strang, R., Blanz, J., Vangrevelinghe, E., Berghausen, J., Lee, C.C., Zerwes, H.-G.

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

2015-08-05T19:08:28Z

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

←Older revision

Revision as of 19:08, 5 August 2015

OCA: New page: '''Unreleased structure''' The entry 5cxz is ON HOLD Authors: Thoma, G., Veenstra, S., Strang, R., Blanz, J., Vangrevelinghe, E., Berghausen, J., Lee, C.C., Zerwes, H.-G. Description: ...

2015-08-05T19:08:27Z

New page: '''Unreleased structure''' The entry 5cxz is ON HOLD Authors: Thoma, G., Veenstra, S., Strang, R., Blanz, J., Vangrevelinghe, E., Berghausen, J., Lee, C.C., Zerwes, H.-G. Description: ...

New page

'''Unreleased structure'''

The entry 5cxz is ON HOLD

Authors: Thoma, G., Veenstra, S., Strang, R., Blanz, J., Vangrevelinghe, E., Berghausen, J., Lee, C.C., Zerwes, H.-G.

Description: SYK catalytic domain complexed with naphthyridine inhibitor
[[Category: Unreleased Structures]]
[[Category: Berghausen, J]]
[[Category: Thoma, G]]
[[Category: Blanz, J]]
[[Category: Strang, R]]
[[Category: Lee, C.C]]
[[Category: Veenstra, S]]
[[Category: Zerwes, H.-G]]
[[Category: Vangrevelinghe, E]]