4rfz - Revision history

OCA at 17:49, 20 September 2023

OCA — Wed, 20 Sep 2023 17:49:41 GMT

←Older revision		Revision as of 17:49, 20 September 2023
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	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4rfz]] 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=4RFZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4RFZ FirstGlance]. <br>		<table><tr><td colspan='2'>[[4rfz]] 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=4RFZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4RFZ FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3OV:6-(DIMETHYLAMINO)-8-FLUORO-2-[2-(HYDROXYMETHYL)-3-(1-METHYL-5-{[5-(MORPHOLIN-4-YLCARBONYL)PYRIDIN-2-YL]AMINO}-6-OXO-1,6-DIHYDROPYRIDIN-3-YL)PHENYL]ISOQUINOLIN-1(2H)-ONE'>3OV</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</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]] 1.17Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3OV:6-(DIMETHYLAMINO)-8-FLUORO-2-[2-(HYDROXYMETHYL)-3-(1-METHYL-5-{[5-(MORPHOLIN-4-YLCARBONYL)PYRIDIN-2-YL]AMINO}-6-OXO-1,6-DIHYDROPYRIDIN-3-YL)PHENYL]ISOQUINOLIN-1(2H)-ONE'>3OV</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</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=4rfz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rfz OCA], [https://pdbe.org/4rfz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4rfz RCSB], [https://www.ebi.ac.uk/pdbsum/4rfz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4rfz 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=4rfz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rfz OCA], [https://pdbe.org/4rfz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4rfz RCSB], [https://www.ebi.ac.uk/pdbsum/4rfz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4rfz ProSAT]</span></td></tr>
	</table>		</table>

OCA at 06:54, 2 March 2023

OCA — Thu, 02 Mar 2023 06:54:03 GMT

←Older revision		Revision as of 06:54, 2 March 2023
Line 3:		Line 3:
	<StructureSection load='4rfz' size='340' side='right'caption='[[4rfz]], [[Resolution\|resolution]] 1.17Å' scene=''>		<StructureSection load='4rfz' size='340' side='right'caption='[[4rfz]], [[Resolution\|resolution]] 1.17Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4rfz]] 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=4RFZ OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4RFZ FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4rfz]] 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=4RFZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4RFZ FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3OV:6-(DIMETHYLAMINO)-8-FLUORO-2-[2-(HYDROXYMETHYL)-3-(1-METHYL-5-{[5-(MORPHOLIN-4-YLCARBONYL)PYRIDIN-2-YL]AMINO}-6-OXO-1,6-DIHYDROPYRIDIN-3-YL)PHENYL]ISOQUINOLIN-1(2H)-ONE'>3OV</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene~~></td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3OV:6-(DIMETHYLAMINO)-8-FLUORO-2-[2-(HYDROXYMETHYL)-3-(1-METHYL-5-{[5-(MORPHOLIN-4-YLCARBONYL)PYRIDIN-2-YL]AMINO}-6-OXO-1,6-DIHYDROPYRIDIN-3-YL)PHENYL]ISOQUINOLIN-1(2H)-ONE'>3OV</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene></td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4otr\|4otr]], [[4rfy\|4rfy]], [[4rg0\|4rg0]]</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=4rfz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rfz OCA], [https://pdbe.org/4rfz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4rfz RCSB], [https://www.ebi.ac.uk/pdbsum/4rfz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4rfz ProSAT]</span></td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">BTK, AGMX1, ATK, BPK ([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~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4rfz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rfz OCA], [~~http~~://pdbe.org/4rfz PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4rfz RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4rfz PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4rfz 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 ==
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	==See Also==		==See Also==
-	*[[Tyrosine kinase\|Tyrosine kinase]]	+	*[[Tyrosine kinase 3D structures\|Tyrosine 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: Kuglstatter A]]
-	[[Category: Kuglstatter, A]]	+	[[Category: Wong A]]
-	[[Category: Wong, A]]	+
-	~~[[Category: Transferase-transferase inhibitor complex~~]]	+

OCA at 10:00, 1 May 2019

OCA — Wed, 01 May 2019 10:00:27 GMT

←Older revision		Revision as of 10:00, 1 May 2019
Line 1:		Line 1:

	==Crystal structure of BTK kinase domain complexed with 6-(dimethylamino)-8-fluoro-2-[2-(hydroxymethyl)-3-[1-methyl-5-[[5-(morpholine-4-carbonyl)-2-pyridyl]amino]-6-oxo-3-pyridyl]phenyl]isoquinolin-1-one==		==Crystal structure of BTK kinase domain complexed with 6-(dimethylamino)-8-fluoro-2-[2-(hydroxymethyl)-3-[1-methyl-5-[[5-(morpholine-4-carbonyl)-2-pyridyl]amino]-6-oxo-3-pyridyl]phenyl]isoquinolin-1-one==
-	<StructureSection load='4rfz' size='340' side='right' caption='[[4rfz]], [[Resolution\|resolution]] 1.17Å' scene=''>	+	<StructureSection load='4rfz' size='340' side='right'caption='[[4rfz]], [[Resolution\|resolution]] 1.17Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4rfz]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4RFZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4RFZ FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4rfz]] 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=4RFZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4RFZ FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3OV:6-(DIMETHYLAMINO)-8-FLUORO-2-[2-(HYDROXYMETHYL)-3-(1-METHYL-5-{[5-(MORPHOLIN-4-YLCARBONYL)PYRIDIN-2-YL]AMINO}-6-OXO-1,6-DIHYDROPYRIDIN-3-YL)PHENYL]ISOQUINOLIN-1(2H)-ONE'>3OV</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3OV:6-(DIMETHYLAMINO)-8-FLUORO-2-[2-(HYDROXYMETHYL)-3-(1-METHYL-5-{[5-(MORPHOLIN-4-YLCARBONYL)PYRIDIN-2-YL]AMINO}-6-OXO-1,6-DIHYDROPYRIDIN-3-YL)PHENYL]ISOQUINOLIN-1(2H)-ONE'>3OV</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4otr\|4otr]], [[4rfy\|4rfy]], [[4rg0\|4rg0]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4otr\|4otr]], [[4rfy\|4rfy]], [[4rg0\|4rg0]]</td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">BTK, AGMX1, ATK, BPK ([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=4rfz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rfz OCA], [http://pdbe.org/4rfz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4rfz RCSB], [http://www.ebi.ac.uk/pdbsum/4rfz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4rfz 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=4rfz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rfz OCA], [http://pdbe.org/4rfz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4rfz RCSB], [http://www.ebi.ac.uk/pdbsum/4rfz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4rfz ProSAT]</span></td></tr>
Line 29:		Line 30:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Non-specific protein-tyrosine kinase]]		[[Category: Non-specific protein-tyrosine kinase]]
	[[Category: Kuglstatter, A]]		[[Category: Kuglstatter, A]]
	[[Category: Wong, A]]		[[Category: Wong, A]]
	[[Category: Transferase-transferase inhibitor complex]]		[[Category: Transferase-transferase inhibitor complex]]

OCA at 11:47, 11 August 2016

OCA — Thu, 11 Aug 2016 11:47:29 GMT

←Older revision		Revision as of 11:47, 11 August 2016
Line 1:		Line 1:
		+
	==Crystal structure of BTK kinase domain complexed with 6-(dimethylamino)-8-fluoro-2-[2-(hydroxymethyl)-3-[1-methyl-5-[[5-(morpholine-4-carbonyl)-2-pyridyl]amino]-6-oxo-3-pyridyl]phenyl]isoquinolin-1-one==		==Crystal structure of BTK kinase domain complexed with 6-(dimethylamino)-8-fluoro-2-[2-(hydroxymethyl)-3-[1-methyl-5-[[5-(morpholine-4-carbonyl)-2-pyridyl]amino]-6-oxo-3-pyridyl]phenyl]isoquinolin-1-one==
	<StructureSection load='4rfz' size='340' side='right' caption='[[4rfz]], [[Resolution\|resolution]] 1.17Å' scene=''>		<StructureSection load='4rfz' size='340' side='right' caption='[[4rfz]], [[Resolution\|resolution]] 1.17Å' scene=''>
Line 6:		Line 7:
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4otr\|4otr]], [[4rfy\|4rfy]], [[4rg0\|4rg0]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4otr\|4otr]], [[4rfy\|4rfy]], [[4rg0\|4rg0]]</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=4rfz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rfz OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4rfz RCSB], [http://www.ebi.ac.uk/pdbsum/4rfz 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=4rfz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rfz OCA], [http://pdbe.org/4rfz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4rfz RCSB], [http://www.ebi.ac.uk/pdbsum/4rfz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4rfz ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 20:		Line 21:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
		+	<div class="pdbe-citations 4rfz" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Tyrosine kinase\|Tyrosine kinase]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 10:54, 24 December 2014

OCA — Wed, 24 Dec 2014 10:54:14 GMT

←Older revision		Revision as of 10:54, 24 December 2014
Line 1:		Line 1:
-	'''~~Unreleased~~ structure'''	+	==Crystal structure of BTK kinase domain complexed with 6-(dimethylamino)-8-fluoro-2-[2-(hydroxymethyl)-3-[1-methyl-5-[[5-(morpholine-4-carbonyl)-2-pyridyl]amino]-6-oxo-3-pyridyl]phenyl]isoquinolin-1-one==
		+	<StructureSection load='4rfz' size='340' side='right' caption='[[4rfz]], [[Resolution\|resolution]] 1.17Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[4rfz]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4RFZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4RFZ FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3OV:6-(DIMETHYLAMINO)-8-FLUORO-2-[2-(HYDROXYMETHYL)-3-(1-METHYL-5-{[5-(MORPHOLIN-4-YLCARBONYL)PYRIDIN-2-YL]AMINO}-6-OXO-1,6-DIHYDROPYRIDIN-3-YL)PHENYL]ISOQUINOLIN-1(2H)-ONE'>3OV</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4otr\|4otr]], [[4rfy\|4rfy]], [[4rg0\|4rg0]]</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=4rfz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rfz OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4rfz RCSB], [http://www.ebi.ac.uk/pdbsum/4rfz PDBsum]</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 ==
		+	A rational fluorine scan based on co-crystal structures was explored to increase the potency of a series of selective BTK inhibitors. While fluorine substitution on a saturated bicyclic ring system yields no apparent benefit, the same operation on an unsaturated bicyclic ring can increase HWB activity by up to 40-fold. Comparison of co-crystal structures of parent molecules and fluorinated counterparts revealed the importance of placing fluorine at the optimal position to achieve favorable interactions with protein side chains.

-	~~The entry 4rfz is ON HOLD until Paper Publication~~	+	Finding the perfect spot for fluorine: Improving potency up to 40-fold during a rational fluorine scan of a Bruton's Tyrosine Kinase (BTK) inhibitor scaffold.,Lou Y, Sweeney ZK, Kuglstatter A, Davis D, Goldstein DM, Han X, Hong J, Kocer B, Kondru RK, Litman R, McIntosh J, Sarma K, Suh J, Taygerly J, Owens TD Bioorg Med Chem Lett. 2014 Nov 20. pii: S0960-894X(14)01214-1. doi:, 10.1016/j.bmcl.2014.11.030. PMID:25466710<ref>PMID:25466710</ref>

-	~~Authors: Kuglstatter~~, A.~~, Wong, A~~.	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-		+	</div>
-	~~Description~~: ~~Crystal structure of BTK kinase domain complexed with 6~~-~~(dimethylamino)-8-fluoro-2~~-[~~2-(hydroxymethyl)-3-~~[~~1-methyl-5-~~[[~~5-(morpholine-4-carbonyl)-2-pyridyl~~]~~amino~~]-~~6-oxo-3-pyridyl~~]~~phenyl~~]~~isoquinolin-1-one~~	+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Non-specific protein-tyrosine kinase]]
		+	[[Category: Kuglstatter, A]]
		+	[[Category: Wong, A]]
		+	[[Category: Transferase-transferase inhibitor complex]]

OCA at 09:27, 20 October 2014

OCA — Mon, 20 Oct 2014 09:27:49 GMT

←Older revision		Revision as of 09:27, 20 October 2014
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 4rfz is ON HOLD	+	The entry 4rfz is ON HOLD until Paper Publication

	Authors: Kuglstatter, A., Wong, A.		Authors: Kuglstatter, A., Wong, A.

	Description: Crystal structure of BTK kinase domain complexed with 6-(dimethylamino)-8-fluoro-2-[2-(hydroxymethyl)-3-[1-methyl-5-[[5-(morpholine-4-carbonyl)-2-pyridyl]amino]-6-oxo-3-pyridyl]phenyl]isoquinolin-1-one		Description: Crystal structure of BTK kinase domain complexed with 6-(dimethylamino)-8-fluoro-2-[2-(hydroxymethyl)-3-[1-methyl-5-[[5-(morpholine-4-carbonyl)-2-pyridyl]amino]-6-oxo-3-pyridyl]phenyl]isoquinolin-1-one

OCA: Protected "4rfz" [edit=sysop:move=sysop]

OCA — Wed, 08 Oct 2014 06:33:25 GMT

Protected "4rfz" [edit=sysop:move=sysop]

←Older revision

Revision as of 06:33, 8 October 2014

OCA: New page: '''Unreleased structure''' The entry 4rfz is ON HOLD Authors: Kuglstatter, A., Wong, A. Description: Crystal structure of BTK kinase domain complexed with 6-(dimethylamino)-8-fluoro-2-...

OCA — Wed, 08 Oct 2014 06:33:24 GMT

New page: '''Unreleased structure''' The entry 4rfz is ON HOLD Authors: Kuglstatter, A., Wong, A. Description: Crystal structure of BTK kinase domain complexed with 6-(dimethylamino)-8-fluoro-2-...

New page

'''Unreleased structure'''

The entry 4rfz is ON HOLD

Authors: Kuglstatter, A., Wong, A.

Description: Crystal structure of BTK kinase domain complexed with 6-(dimethylamino)-8-fluoro-2-[2-(hydroxymethyl)-3-[1-methyl-5-[[5-(morpholine-4-carbonyl)-2-pyridyl]amino]-6-oxo-3-pyridyl]phenyl]isoquinolin-1-one