5bq0 - Revision history

OCA at 12:17, 6 March 2024

OCA — Wed, 06 Mar 2024 12:17:37 GMT

←Older revision		Revision as of 12:17, 6 March 2024
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[5bq0]] 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=5BQ0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5BQ0 FirstGlance]. <br>		<table><tr><td colspan='2'>[[5bq0]] 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=5BQ0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5BQ0 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4US:4-(2-CHLOROPHENYL)-7-[(4-METHYLPIPERAZIN-1-YL)CARBONYL]-9H-CARBAZOLE-1-CARBOXAMIDE'>4US</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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]] 1.57Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4US:4-(2-CHLOROPHENYL)-7-[(4-METHYLPIPERAZIN-1-YL)CARBONYL]-9H-CARBAZOLE-1-CARBOXAMIDE'>4US</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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=5bq0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5bq0 OCA], [https://pdbe.org/5bq0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5bq0 RCSB], [https://www.ebi.ac.uk/pdbsum/5bq0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5bq0 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=5bq0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5bq0 OCA], [https://pdbe.org/5bq0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5bq0 RCSB], [https://www.ebi.ac.uk/pdbsum/5bq0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5bq0 ProSAT]</span></td></tr>
	</table>		</table>
Line 11:		Line 12:
	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/BTK_HUMAN BTK_HUMAN] Non-receptor tyrosine kinase indispensable for B lymphocyte development, differentiation and signaling. Binding of antigen to the B-cell antigen receptor (BCR) triggers signaling that ultimately leads to B-cell activation. After BCR engagement and activation at the plasma membrane, phosphorylates PLCG2 at several sites, igniting the downstream signaling pathway through calcium mobilization, followed by activation of the protein kinase C (PKC) family members. PLCG2 phosphorylation is performed in close cooperation with the adapter protein B-cell linker protein BLNK. BTK acts as a platform to bring together a diverse array of signaling proteins and is implicated in cytokine receptor signaling pathways. Plays an important role in the function of immune cells of innate as well as adaptive immunity, as a component of the Toll-like receptors (TLR) pathway. The TLR pathway acts as a primary surveillance system for the detection of pathogens and are crucial to the activation of host defense. Especially, is a critical molecule in regulating TLR9 activation in splenic B-cells. Within the TLR pathway, induces tyrosine phosphorylation of TIRAP which leads to TIRAP degradation. BTK plays also a critical role in transcription regulation. Induces the activity of NF-kappa-B, which is involved in regulating the expression of hundreds of genes. BTK is involved on the signaling pathway linking TLR8 and TLR9 to NF-kappa-B. Transiently phosphorylates transcription factor GTF2I on tyrosine residues in response to BCR. GTF2I then translocates to the nucleus to bind regulatory enhancer elements to modulate gene expression. ARID3A and NFAT are other transcriptional target of BTK. BTK is required for the formation of functional ARID3A DNA-binding complexes. There is however no evidence that BTK itself binds directly to DNA. BTK has a dual role in the regulation of apoptosis.<ref>PMID:9012831</ref> <ref>PMID:11606584</ref> <ref>PMID:16517732</ref> <ref>PMID:16738337</ref> <ref>PMID:16415872</ref> <ref>PMID:17932028</ref>		[https://www.uniprot.org/uniprot/BTK_HUMAN BTK_HUMAN] Non-receptor tyrosine kinase indispensable for B lymphocyte development, differentiation and signaling. Binding of antigen to the B-cell antigen receptor (BCR) triggers signaling that ultimately leads to B-cell activation. After BCR engagement and activation at the plasma membrane, phosphorylates PLCG2 at several sites, igniting the downstream signaling pathway through calcium mobilization, followed by activation of the protein kinase C (PKC) family members. PLCG2 phosphorylation is performed in close cooperation with the adapter protein B-cell linker protein BLNK. BTK acts as a platform to bring together a diverse array of signaling proteins and is implicated in cytokine receptor signaling pathways. Plays an important role in the function of immune cells of innate as well as adaptive immunity, as a component of the Toll-like receptors (TLR) pathway. The TLR pathway acts as a primary surveillance system for the detection of pathogens and are crucial to the activation of host defense. Especially, is a critical molecule in regulating TLR9 activation in splenic B-cells. Within the TLR pathway, induces tyrosine phosphorylation of TIRAP which leads to TIRAP degradation. BTK plays also a critical role in transcription regulation. Induces the activity of NF-kappa-B, which is involved in regulating the expression of hundreds of genes. BTK is involved on the signaling pathway linking TLR8 and TLR9 to NF-kappa-B. Transiently phosphorylates transcription factor GTF2I on tyrosine residues in response to BCR. GTF2I then translocates to the nucleus to bind regulatory enhancer elements to modulate gene expression. ARID3A and NFAT are other transcriptional target of BTK. BTK is required for the formation of functional ARID3A DNA-binding complexes. There is however no evidence that BTK itself binds directly to DNA. BTK has a dual role in the regulation of apoptosis.<ref>PMID:9012831</ref> <ref>PMID:11606584</ref> <ref>PMID:16517732</ref> <ref>PMID:16738337</ref> <ref>PMID:16415872</ref> <ref>PMID:17932028</ref>
-	<div style="background-color:#fffaf0;">
-	== Publication Abstract from PubMed ==
-	Four series of disubstituted carbazole-1-carboxamides were designed and synthesised as inhibitors of Bruton's tyrosine kinase (BTK). 4,7- and 4,6-disubstituted carbazole-1-carboxamides were potent and selective inhibitors of BTK, while 3,7- and 3,6-disubstituted carbazole-1-carboxamides were potent and selective inhibitors of Janus kinase 2 (JAK2).
-
-	Design and synthesis of carbazole carboxamides as promising inhibitors of Bruton's tyrosine kinase (BTK) and Janus kinase 2 (JAK2).,Liu Q, Batt DG, Lippy JS, Surti N, Tebben AJ, Muckelbauer JK, Chen L, An Y, Chang C, Pokross M, Yang Z, Wang H, Burke JR, Carter PH, Tino JA Bioorg Med Chem Lett. 2015 Oct 1;25(19):4265-9. doi: 10.1016/j.bmcl.2015.07.102. , Epub 2015 Aug 6. PMID:26320619<ref>PMID:26320619</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 5bq0" style="background-color:#fffaf0;"></div>

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

OCA at 06:03, 7 June 2023

OCA — Wed, 07 Jun 2023 06:03:22 GMT

←Older revision		Revision as of 06:03, 7 June 2023
Line 3:		Line 3:
	<StructureSection load='5bq0' size='340' side='right'caption='[[5bq0]], [[Resolution\|resolution]] 1.57Å' scene=''>		<StructureSection load='5bq0' size='340' side='right'caption='[[5bq0]], [[Resolution\|resolution]] 1.57Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5bq0]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5BQ0 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5BQ0 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5bq0]] 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=5BQ0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5BQ0 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4US:4-(2-CHLOROPHENYL)-7-[(4-METHYLPIPERAZIN-1-YL)CARBONYL]-9H-CARBAZOLE-1-CARBOXAMIDE'>4US</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene~~></td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4US:4-(2-CHLOROPHENYL)-7-[(4-METHYLPIPERAZIN-1-YL)CARBONYL]-9H-CARBAZOLE-1-CARBOXAMIDE'>4US</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5bpy\|5bpy]]</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=5bq0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5bq0 OCA], [https://pdbe.org/5bq0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5bq0 RCSB], [https://www.ebi.ac.uk/pdbsum/5bq0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5bq0 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=5bq0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5bq0 OCA], [~~http~~://pdbe.org/5bq0 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5bq0 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5bq0 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5bq0 ProSAT]</span></td></tr>	+
	</table>		</table>
	== Disease ==		== Disease ==
-	[~~[http~~://www.uniprot.org/uniprot/BTK_HUMAN BTK_HUMAN]] Defects in BTK are the cause of X-linked agammaglobulinemia (XLA) [MIM:[~~http~~://omim.org/entry/300755 300755]]; also known as X-linked agammaglobulinemia type 1 (AGMX1) or immunodeficiency type 1 (IMD1). XLA is a humoral immunodeficiency disease which results in developmental defects in the maturation pathway of B-cells. Affected boys have normal levels of pre-B-cells in their bone marrow but virtually no circulating mature B-lymphocytes. This results in a lack of immunoglobulins of all classes and leads to recurrent bacterial infections like otitis, conjunctivitis, dermatitis, sinusitis in the first few years of life, or even some patients present overwhelming sepsis or meningitis, resulting in death in a few hours. Treatment in most cases is by infusion of intravenous immunoglobulin.<ref>PMID:7880320</ref> <ref>PMID:8013627</ref> <ref>PMID:8162056</ref> <ref>PMID:8162018</ref> <ref>PMID:7849697</ref> <ref>PMID:7849721</ref> <ref>PMID:7809124</ref> <ref>PMID:7849006</ref> <ref>PMID:7711734</ref> <ref>PMID:7633420</ref> <ref>PMID:7633429</ref> <ref>PMID:8634718</ref> <ref>PMID:7627183</ref> <ref>PMID:7897635</ref> <ref>PMID:8723128</ref> <ref>PMID:8695804</ref> <ref>PMID:8834236</ref> <ref>PMID:9280283</ref> <ref>PMID:9260159</ref> <ref>PMID:9545398</ref> <ref>PMID:9445504</ref> <ref>PMID:10220140</ref> <ref>PMID:10678660</ref> <ref>PMID:10612838</ref> Defects in BTK may be the cause of X-linked hypogammaglobulinemia and isolated growth hormone deficiency (XLA-IGHD) [MIM:[~~http~~://omim.org/entry/307200 307200]]; also known as agammaglobulinemia and isolated growth hormone deficiency or Fleisher syndrome or isolated growth hormone deficiency type 3 (IGHD3). In rare cases XLA is inherited together with isolated growth hormone deficiency (IGHD).	+	[https://www.uniprot.org/uniprot/BTK_HUMAN BTK_HUMAN] Defects in BTK are the cause of X-linked agammaglobulinemia (XLA) [MIM:[https://omim.org/entry/300755 300755]; also known as X-linked agammaglobulinemia type 1 (AGMX1) or immunodeficiency type 1 (IMD1). XLA is a humoral immunodeficiency disease which results in developmental defects in the maturation pathway of B-cells. Affected boys have normal levels of pre-B-cells in their bone marrow but virtually no circulating mature B-lymphocytes. This results in a lack of immunoglobulins of all classes and leads to recurrent bacterial infections like otitis, conjunctivitis, dermatitis, sinusitis in the first few years of life, or even some patients present overwhelming sepsis or meningitis, resulting in death in a few hours. Treatment in most cases is by infusion of intravenous immunoglobulin.<ref>PMID:7880320</ref> <ref>PMID:8013627</ref> <ref>PMID:8162056</ref> <ref>PMID:8162018</ref> <ref>PMID:7849697</ref> <ref>PMID:7849721</ref> <ref>PMID:7809124</ref> <ref>PMID:7849006</ref> <ref>PMID:7711734</ref> <ref>PMID:7633420</ref> <ref>PMID:7633429</ref> <ref>PMID:8634718</ref> <ref>PMID:7627183</ref> <ref>PMID:7897635</ref> <ref>PMID:8723128</ref> <ref>PMID:8695804</ref> <ref>PMID:8834236</ref> <ref>PMID:9280283</ref> <ref>PMID:9260159</ref> <ref>PMID:9545398</ref> <ref>PMID:9445504</ref> <ref>PMID:10220140</ref> <ref>PMID:10678660</ref> <ref>PMID:10612838</ref> Defects in BTK may be the cause of X-linked hypogammaglobulinemia and isolated growth hormone deficiency (XLA-IGHD) [MIM:[https://omim.org/entry/307200 307200]; also known as agammaglobulinemia and isolated growth hormone deficiency or Fleisher syndrome or isolated growth hormone deficiency type 3 (IGHD3). In rare cases XLA is inherited together with isolated growth hormone deficiency (IGHD).
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/BTK_HUMAN BTK_HUMAN]] Non-receptor tyrosine kinase indispensable for B lymphocyte development, differentiation and signaling. Binding of antigen to the B-cell antigen receptor (BCR) triggers signaling that ultimately leads to B-cell activation. After BCR engagement and activation at the plasma membrane, phosphorylates PLCG2 at several sites, igniting the downstream signaling pathway through calcium mobilization, followed by activation of the protein kinase C (PKC) family members. PLCG2 phosphorylation is performed in close cooperation with the adapter protein B-cell linker protein BLNK. BTK acts as a platform to bring together a diverse array of signaling proteins and is implicated in cytokine receptor signaling pathways. Plays an important role in the function of immune cells of innate as well as adaptive immunity, as a component of the Toll-like receptors (TLR) pathway. The TLR pathway acts as a primary surveillance system for the detection of pathogens and are crucial to the activation of host defense. Especially, is a critical molecule in regulating TLR9 activation in splenic B-cells. Within the TLR pathway, induces tyrosine phosphorylation of TIRAP which leads to TIRAP degradation. BTK plays also a critical role in transcription regulation. Induces the activity of NF-kappa-B, which is involved in regulating the expression of hundreds of genes. BTK is involved on the signaling pathway linking TLR8 and TLR9 to NF-kappa-B. Transiently phosphorylates transcription factor GTF2I on tyrosine residues in response to BCR. GTF2I then translocates to the nucleus to bind regulatory enhancer elements to modulate gene expression. ARID3A and NFAT are other transcriptional target of BTK. BTK is required for the formation of functional ARID3A DNA-binding complexes. There is however no evidence that BTK itself binds directly to DNA. BTK has a dual role in the regulation of apoptosis.<ref>PMID:9012831</ref> <ref>PMID:11606584</ref> <ref>PMID:16517732</ref> <ref>PMID:16738337</ref> <ref>PMID:16415872</ref> <ref>PMID:17932028</ref>	+	[https://www.uniprot.org/uniprot/BTK_HUMAN BTK_HUMAN] Non-receptor tyrosine kinase indispensable for B lymphocyte development, differentiation and signaling. Binding of antigen to the B-cell antigen receptor (BCR) triggers signaling that ultimately leads to B-cell activation. After BCR engagement and activation at the plasma membrane, phosphorylates PLCG2 at several sites, igniting the downstream signaling pathway through calcium mobilization, followed by activation of the protein kinase C (PKC) family members. PLCG2 phosphorylation is performed in close cooperation with the adapter protein B-cell linker protein BLNK. BTK acts as a platform to bring together a diverse array of signaling proteins and is implicated in cytokine receptor signaling pathways. Plays an important role in the function of immune cells of innate as well as adaptive immunity, as a component of the Toll-like receptors (TLR) pathway. The TLR pathway acts as a primary surveillance system for the detection of pathogens and are crucial to the activation of host defense. Especially, is a critical molecule in regulating TLR9 activation in splenic B-cells. Within the TLR pathway, induces tyrosine phosphorylation of TIRAP which leads to TIRAP degradation. BTK plays also a critical role in transcription regulation. Induces the activity of NF-kappa-B, which is involved in regulating the expression of hundreds of genes. BTK is involved on the signaling pathway linking TLR8 and TLR9 to NF-kappa-B. Transiently phosphorylates transcription factor GTF2I on tyrosine residues in response to BCR. GTF2I then translocates to the nucleus to bind regulatory enhancer elements to modulate gene expression. ARID3A and NFAT are other transcriptional target of BTK. BTK is required for the formation of functional ARID3A DNA-binding complexes. There is however no evidence that BTK itself binds directly to DNA. BTK has a dual role in the regulation of apoptosis.<ref>PMID:9012831</ref> <ref>PMID:11606584</ref> <ref>PMID:16517732</ref> <ref>PMID:16738337</ref> <ref>PMID:16415872</ref> <ref>PMID:17932028</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 29:		Line 27:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Non-specific protein-tyrosine kinase]]~~	+	[[Category: Muckelbauer JK]]
-	[[Category: Muckelbauer~~, J K]]~~	+
-	~~[[Category: Inhibitor]]~~	+
-	~~[[Category: Kinase]]~~	+
-	~~[[Category: Transferase]]~~	+
-	~~[[Category: Transferase-transferase inhibitor complex~~]]	+

OCA at 08:53, 11 March 2020

OCA — Wed, 11 Mar 2020 08:53:59 GMT

←Older revision		Revision as of 08:53, 11 March 2020
Line 1:		Line 1:

	==Crystal structure of bruton agammaglobulinemia tyrosine kinase complexed with BMS-824171 AKA 6-[(3R)-3-(4-tert-bu tylbenzamido)piperidin-1-yl]-2-{[4-(morpholine-4-carbonyl) phenyl]amino}pyridine-3-carboxamide==		==Crystal structure of bruton agammaglobulinemia tyrosine kinase complexed with BMS-824171 AKA 6-[(3R)-3-(4-tert-bu tylbenzamido)piperidin-1-yl]-2-{[4-(morpholine-4-carbonyl) phenyl]amino}pyridine-3-carboxamide==
-	<StructureSection load='5bq0' size='340' side='right' caption='[[5bq0]], [[Resolution\|resolution]] 1.57Å' scene=''>	+	<StructureSection load='5bq0' size='340' side='right'caption='[[5bq0]], [[Resolution\|resolution]] 1.57Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[5bq0]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5BQ0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5BQ0 FirstGlance]. <br>		<table><tr><td colspan='2'>[[5bq0]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5BQ0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5BQ0 FirstGlance]. <br>
Line 22:		Line 22:
	</div>		</div>
	<div class="pdbe-citations 5bq0" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 5bq0" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Tyrosine kinase 3D structures\|Tyrosine kinase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Large Structures]]
	[[Category: Non-specific protein-tyrosine kinase]]		[[Category: Non-specific protein-tyrosine kinase]]
	[[Category: Muckelbauer, J K]]		[[Category: Muckelbauer, J K]]

OCA at 15:40, 16 November 2017

OCA — Thu, 16 Nov 2017 15:40:22 GMT

←Older revision		Revision as of 15:40, 16 November 2017
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 5bq0 is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Crystal structure of bruton agammaglobulinemia tyrosine kinase complexed with BMS-824171 AKA 6-[(3R)-3-(4-tert-bu tylbenzamido)piperidin-1-yl]-2-{[4-(morpholine-4-carbonyl) phenyl]amino}pyridine-3-carboxamide==
		+	<StructureSection load='5bq0' size='340' side='right' caption='[[5bq0]], [[Resolution\|resolution]] 1.57Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5bq0]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5BQ0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5BQ0 FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4US:4-(2-CHLOROPHENYL)-7-[(4-METHYLPIPERAZIN-1-YL)CARBONYL]-9H-CARBAZOLE-1-CARBOXAMIDE'>4US</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5bpy\|5bpy]]</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=5bq0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5bq0 OCA], [http://pdbe.org/5bq0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5bq0 RCSB], [http://www.ebi.ac.uk/pdbsum/5bq0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5bq0 ProSAT]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/BTK_HUMAN BTK_HUMAN]] Defects in BTK are the cause of X-linked agammaglobulinemia (XLA) [MIM:[http://omim.org/entry/300755 300755]]; also known as X-linked agammaglobulinemia type 1 (AGMX1) or immunodeficiency type 1 (IMD1). XLA is a humoral immunodeficiency disease which results in developmental defects in the maturation pathway of B-cells. Affected boys have normal levels of pre-B-cells in their bone marrow but virtually no circulating mature B-lymphocytes. This results in a lack of immunoglobulins of all classes and leads to recurrent bacterial infections like otitis, conjunctivitis, dermatitis, sinusitis in the first few years of life, or even some patients present overwhelming sepsis or meningitis, resulting in death in a few hours. Treatment in most cases is by infusion of intravenous immunoglobulin.<ref>PMID:7880320</ref> <ref>PMID:8013627</ref> <ref>PMID:8162056</ref> <ref>PMID:8162018</ref> <ref>PMID:7849697</ref> <ref>PMID:7849721</ref> <ref>PMID:7809124</ref> <ref>PMID:7849006</ref> <ref>PMID:7711734</ref> <ref>PMID:7633420</ref> <ref>PMID:7633429</ref> <ref>PMID:8634718</ref> <ref>PMID:7627183</ref> <ref>PMID:7897635</ref> <ref>PMID:8723128</ref> <ref>PMID:8695804</ref> <ref>PMID:8834236</ref> <ref>PMID:9280283</ref> <ref>PMID:9260159</ref> <ref>PMID:9545398</ref> <ref>PMID:9445504</ref> <ref>PMID:10220140</ref> <ref>PMID:10678660</ref> <ref>PMID:10612838</ref> Defects in BTK may be the cause of X-linked hypogammaglobulinemia and isolated growth hormone deficiency (XLA-IGHD) [MIM:[http://omim.org/entry/307200 307200]]; also known as agammaglobulinemia and isolated growth hormone deficiency or Fleisher syndrome or isolated growth hormone deficiency type 3 (IGHD3). In rare cases XLA is inherited together with isolated growth hormone deficiency (IGHD).
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/BTK_HUMAN BTK_HUMAN]] Non-receptor tyrosine kinase indispensable for B lymphocyte development, differentiation and signaling. Binding of antigen to the B-cell antigen receptor (BCR) triggers signaling that ultimately leads to B-cell activation. After BCR engagement and activation at the plasma membrane, phosphorylates PLCG2 at several sites, igniting the downstream signaling pathway through calcium mobilization, followed by activation of the protein kinase C (PKC) family members. PLCG2 phosphorylation is performed in close cooperation with the adapter protein B-cell linker protein BLNK. BTK acts as a platform to bring together a diverse array of signaling proteins and is implicated in cytokine receptor signaling pathways. Plays an important role in the function of immune cells of innate as well as adaptive immunity, as a component of the Toll-like receptors (TLR) pathway. The TLR pathway acts as a primary surveillance system for the detection of pathogens and are crucial to the activation of host defense. Especially, is a critical molecule in regulating TLR9 activation in splenic B-cells. Within the TLR pathway, induces tyrosine phosphorylation of TIRAP which leads to TIRAP degradation. BTK plays also a critical role in transcription regulation. Induces the activity of NF-kappa-B, which is involved in regulating the expression of hundreds of genes. BTK is involved on the signaling pathway linking TLR8 and TLR9 to NF-kappa-B. Transiently phosphorylates transcription factor GTF2I on tyrosine residues in response to BCR. GTF2I then translocates to the nucleus to bind regulatory enhancer elements to modulate gene expression. ARID3A and NFAT are other transcriptional target of BTK. BTK is required for the formation of functional ARID3A DNA-binding complexes. There is however no evidence that BTK itself binds directly to DNA. BTK has a dual role in the regulation of apoptosis.<ref>PMID:9012831</ref> <ref>PMID:11606584</ref> <ref>PMID:16517732</ref> <ref>PMID:16738337</ref> <ref>PMID:16415872</ref> <ref>PMID:17932028</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Four series of disubstituted carbazole-1-carboxamides were designed and synthesised as inhibitors of Bruton's tyrosine kinase (BTK). 4,7- and 4,6-disubstituted carbazole-1-carboxamides were potent and selective inhibitors of BTK, while 3,7- and 3,6-disubstituted carbazole-1-carboxamides were potent and selective inhibitors of Janus kinase 2 (JAK2).

-	~~Authors:~~ Muckelbauer, J.K.	+	Design and synthesis of carbazole carboxamides as promising inhibitors of Bruton's tyrosine kinase (BTK) and Janus kinase 2 (JAK2).,Liu Q, Batt DG, Lippy JS, Surti N, Tebben AJ, Muckelbauer JK, Chen L, An Y, Chang C, Pokross M, Yang Z, Wang H, Burke JR, Carter PH, Tino JA Bioorg Med Chem Lett. 2015 Oct 1;25(19):4265-9. doi: 10.1016/j.bmcl.2015.07.102. , Epub 2015 Aug 6. PMID:26320619<ref>PMID:26320619</ref>

-	~~Description: Crystal structure~~ of ~~bruton agammaglobulinemia tyrosine kinase complexed with BMS~~-~~824171 AKA 6~~-[~~(3R)-3~~-(4-~~tert-bu tylbenzamido)piperidin-1-yl~~]~~-2-{~~[~~4-(morpholine-4-carbonyl) phenyl~~]~~amino}pyridine-3-carboxamide~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
-	[[Category: ~~Muckelbauer, J.K~~]]	+	<div class="pdbe-citations 5bq0" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Non-specific protein-tyrosine kinase]]
		+	[[Category: Muckelbauer, J K]]
		+	[[Category: Inhibitor]]
		+	[[Category: Kinase]]
		+	[[Category: Transferase]]
		+	[[Category: Transferase-transferase inhibitor complex]]

OCA at 10:44, 1 July 2015

OCA — Wed, 01 Jul 2015 10:44:03 GMT

←Older revision		Revision as of 10:44, 1 July 2015
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 5bq0 is ON HOLD	+	The entry 5bq0 is ON HOLD until Paper Publication

	Authors: Muckelbauer, J.K.		Authors: Muckelbauer, J.K.

OCA at 12:52, 10 June 2015

OCA — Wed, 10 Jun 2015 12:52:31 GMT

←Older revision		Revision as of 12:52, 10 June 2015
Line 3:		Line 3:
	The entry 5bq0 is ON HOLD		The entry 5bq0 is ON HOLD

-	Authors: ~~JODI~~ K ~~MUCKELBAUER~~	+	Authors: Muckelbauer, J.K.

-	Description: ~~CRYSTAL STRUCTURE OF BRUTON AGAMMAGLOBULINEMIA TYROSINE KINASE COMPLEXED WITH~~ BMS-824171 AKA 6-[(3R)-3-(4-~~TERT~~-~~BU TYLBENZAMIDO~~)~~PIPERIDIN~~-1-YL]-2-{[4-(~~MORPHOLINE~~-4-~~CARBONYL~~) ~~PHENYL~~]~~AMINO~~}~~PYRIDINE~~-3-~~CARBOXAMIDE~~	+	Description: Crystal structure of bruton agammaglobulinemia tyrosine kinase complexed with BMS-824171 AKA 6-[(3R)-3-(4-tert-bu tylbenzamido)piperidin-1-yl]-2-{[4-(morpholine-4-carbonyl) phenyl]amino}pyridine-3-carboxamide
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
-	[[Category: ~~Jodi K~~ Muckelbauer]]	+	[[Category: Muckelbauer, J.K]]

OCA: Protected "5bq0" [edit=sysop:move=sysop]

OCA — Wed, 03 Jun 2015 11:48:01 GMT

Protected "5bq0" [edit=sysop:move=sysop]

←Older revision

Revision as of 11:48, 3 June 2015

OCA: New page: '''Unreleased structure''' The entry 5bq0 is ON HOLD Authors: JODI K MUCKELBAUER Description: CRYSTAL STRUCTURE OF BRUTON AGAMMAGLOBULINEMIA TYROSINE KINASE COMPLEXED WITH BMS-824171 A...

OCA — Wed, 03 Jun 2015 11:48:00 GMT

New page: '''Unreleased structure''' The entry 5bq0 is ON HOLD Authors: JODI K MUCKELBAUER Description: CRYSTAL STRUCTURE OF BRUTON AGAMMAGLOBULINEMIA TYROSINE KINASE COMPLEXED WITH BMS-824171 A...

New page

'''Unreleased structure'''

The entry 5bq0 is ON HOLD

Authors: JODI K MUCKELBAUER

Description: CRYSTAL STRUCTURE OF BRUTON AGAMMAGLOBULINEMIA TYROSINE KINASE COMPLEXED WITH BMS-824171 AKA 6-[(3R)-3-(4-TERT-BU TYLBENZAMIDO)PIPERIDIN-1-YL]-2-{[4-(MORPHOLINE-4-CARBONYL) PHENYL]AMINO}PYRIDINE-3-CARBOXAMIDE
[[Category: Unreleased Structures]]
[[Category: Jodi K Muckelbauer]]