4zlz - Revision history

OCA at 12:16, 6 March 2024

OCA — Wed, 06 Mar 2024 12:16:07 GMT

←Older revision		Revision as of 12:16, 6 March 2024
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4zlz]] 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=4ZLZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ZLZ FirstGlance]. <br>		<table><tr><td colspan='2'>[[4zlz]] 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=4ZLZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ZLZ FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4RV:4-AMINO-8-(4-METHYLPYRIDIN-3-YL)CINNOLINE-3-CARBOXAMIDE'>4RV</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene>, <scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</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]] 2Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4RV:4-AMINO-8-(4-METHYLPYRIDIN-3-YL)CINNOLINE-3-CARBOXAMIDE'>4RV</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene>, <scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</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=4zlz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zlz OCA], [https://pdbe.org/4zlz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4zlz RCSB], [https://www.ebi.ac.uk/pdbsum/4zlz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4zlz 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=4zlz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zlz OCA], [https://pdbe.org/4zlz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4zlz RCSB], [https://www.ebi.ac.uk/pdbsum/4zlz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4zlz 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 ==
-	The discovery and optimization of a series of 4-aminocinnoline-3-carboxamide inhibitors of Bruton's tyrosine kinase are reported. A fragment-based screening approach incorporating X-ray co-crystallography was used to identify a cinnoline fragment and characterize its binding mode in the ATP binding site of Btk. Optimization of the fragment hit resulted in the identification of a lead compound which reduced paw swelling in a dose- and exposure-dependent fashion in a rat model of collagen-induced arthritis.
-
-	Fragment-Based Discovery of a Small Molecule Inhibitor of Bruton's Tyrosine Kinase.,Smith CR, Dougan DR, Komandla M, Kanouni T, Knight BM, Lawson JD, Sabat M, Taylor ER, Vu P, Wyrick C J Med Chem. 2015 Jun 18. PMID:26087137<ref>PMID:26087137</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 4zlz" style="background-color:#fffaf0;"></div>

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

OCA at 07:32, 18 May 2023

OCA — Thu, 18 May 2023 07:32:50 GMT

←Older revision		Revision as of 07:32, 18 May 2023
Line 3:		Line 3:
	<StructureSection load='4zlz' size='340' side='right'caption='[[4zlz]], [[Resolution\|resolution]] 2.00Å' scene=''>		<StructureSection load='4zlz' size='340' side='right'caption='[[4zlz]], [[Resolution\|resolution]] 2.00Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4zlz]] 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=4ZLZ OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4ZLZ FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4zlz]] 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=4ZLZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ZLZ FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4RV:4-AMINO-8-(4-METHYLPYRIDIN-3-YL)CINNOLINE-3-CARBOXAMIDE'>4RV</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene>, <scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene~~></td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4RV:4-AMINO-8-(4-METHYLPYRIDIN-3-YL)CINNOLINE-3-CARBOXAMIDE'>4RV</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene>, <scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene></td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4zly\|4zly]]</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=4zlz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zlz OCA], [https://pdbe.org/4zlz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4zlz RCSB], [https://www.ebi.ac.uk/pdbsum/4zlz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4zlz 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=4zlz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zlz OCA], [~~http~~://pdbe.org/4zlz PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4zlz RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4zlz PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4zlz 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 25:		Line 22:

	==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: Dougan DR]]
-	[[Category: Dougan~~, D R]]~~	+
-	~~[[Category: Cytoplasmic tyrosine kinase]]~~	+
-	~~[[Category: Nuclear factor-kappab]]~~	+
-	~~[[Category: Transcriptional regulation]]~~	+
-	~~[[Category: Transferase-transferase inhibitor complex~~]]	+

OCA at 08:08, 26 June 2019

OCA — Wed, 26 Jun 2019 08:08:32 GMT

←Older revision		Revision as of 08:08, 26 June 2019
Line 1:		Line 1:

	==Crystal Structure of Bruton's Tyrosine Kinase in complex with a substituted Cinnoline==		==Crystal Structure of Bruton's Tyrosine Kinase in complex with a substituted Cinnoline==
-	<StructureSection load='4zlz' size='340' side='right' caption='[[4zlz]], [[Resolution\|resolution]] 2.00Å' scene=''>	+	<StructureSection load='4zlz' size='340' side='right'caption='[[4zlz]], [[Resolution\|resolution]] 2.00Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4zlz]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZLZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZLZ FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4zlz]] 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=4ZLZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZLZ FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4RV:4-AMINO-8-(4-METHYLPYRIDIN-3-YL)CINNOLINE-3-CARBOXAMIDE'>4RV</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene>, <scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4RV:4-AMINO-8-(4-METHYLPYRIDIN-3-YL)CINNOLINE-3-CARBOXAMIDE'>4RV</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene>, <scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4zly\|4zly]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4zly\|4zly]]</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=4zlz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zlz OCA], [http://pdbe.org/4zlz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zlz RCSB], [http://www.ebi.ac.uk/pdbsum/4zlz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4zlz 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=4zlz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zlz OCA], [http://pdbe.org/4zlz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zlz RCSB], [http://www.ebi.ac.uk/pdbsum/4zlz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4zlz ProSAT]</span></td></tr>
Line 22:		Line 23:
	</div>		</div>
	<div class="pdbe-citations 4zlz" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 4zlz" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Tyrosine kinase\|Tyrosine kinase]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Non-specific protein-tyrosine kinase]]		[[Category: Non-specific protein-tyrosine kinase]]
	[[Category: Dougan, D R]]		[[Category: Dougan, D R]]

OCA at 13:19, 10 May 2017

OCA — Wed, 10 May 2017 13:19:00 GMT

←Older revision		Revision as of 13:19, 10 May 2017
Line 1:		Line 1:
		+
	==Crystal Structure of Bruton's Tyrosine Kinase in complex with a substituted Cinnoline==		==Crystal Structure of Bruton's Tyrosine Kinase in complex with a substituted Cinnoline==
	<StructureSection load='4zlz' size='340' side='right' caption='[[4zlz]], [[Resolution\|resolution]] 2.00Å' scene=''>		<StructureSection load='4zlz' size='340' side='right' caption='[[4zlz]], [[Resolution\|resolution]] 2.00Å' scene=''>
Line 6:		Line 7:
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4zly\|4zly]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4zly\|4zly]]</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=4zlz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zlz OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4zlz RCSB], [http://www.ebi.ac.uk/pdbsum/4zlz 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=4zlz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zlz OCA], [http://pdbe.org/4zlz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zlz RCSB], [http://www.ebi.ac.uk/pdbsum/4zlz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4zlz 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 4zlz" style="background-color:#fffaf0;"></div>
	== References ==		== References ==
	<references/>		<references/>

OCA at 12:02, 1 July 2015

OCA — Wed, 01 Jul 2015 12:02:59 GMT

←Older revision		Revision as of 12:02, 1 July 2015
Line 1:		Line 1:
-	'''~~Unreleased~~ structure'''	+	==Crystal Structure of Bruton's Tyrosine Kinase in complex with a substituted Cinnoline==
		+	<StructureSection load='4zlz' size='340' side='right' caption='[[4zlz]], [[Resolution\|resolution]] 2.00Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[4zlz]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZLZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZLZ FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4RV:4-AMINO-8-(4-METHYLPYRIDIN-3-YL)CINNOLINE-3-CARBOXAMIDE'>4RV</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene>, <scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4zly\|4zly]]</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=4zlz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zlz OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4zlz RCSB], [http://www.ebi.ac.uk/pdbsum/4zlz 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 ==
		+	The discovery and optimization of a series of 4-aminocinnoline-3-carboxamide inhibitors of Bruton's tyrosine kinase are reported. A fragment-based screening approach incorporating X-ray co-crystallography was used to identify a cinnoline fragment and characterize its binding mode in the ATP binding site of Btk. Optimization of the fragment hit resulted in the identification of a lead compound which reduced paw swelling in a dose- and exposure-dependent fashion in a rat model of collagen-induced arthritis.

-	~~The entry 4zlz is ON HOLD~~	+	Fragment-Based Discovery of a Small Molecule Inhibitor of Bruton's Tyrosine Kinase.,Smith CR, Dougan DR, Komandla M, Kanouni T, Knight BM, Lawson JD, Sabat M, Taylor ER, Vu P, Wyrick C J Med Chem. 2015 Jun 18. PMID:26087137<ref>PMID:26087137</ref>

-	~~Authors: Dougan~~, D.R.	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-		+	</div>
-	~~Description: Crystal Structure of Bruton's Tyrosine Kinase in complex with a substituted Cinnoline~~	+	== References ==
-	[[Category: ~~Unreleased Structures~~]]	+	<references/>
-	[[Category: Dougan, D.R]]	+	__TOC__
		+	</StructureSection>
		+	[[Category: Non-specific protein-tyrosine kinase]]
		+	[[Category: Dougan, D R]]
		+	[[Category: Cytoplasmic tyrosine kinase]]
		+	[[Category: Nuclear factor-kappab]]
		+	[[Category: Transcriptional regulation]]
		+	[[Category: Transferase-transferase inhibitor complex]]

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

OCA — Wed, 13 May 2015 11:06:38 GMT

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

←Older revision

Revision as of 11:06, 13 May 2015

OCA: New page: '''Unreleased structure''' The entry 4zlz is ON HOLD Authors: Dougan, D.R. Description: Crystal Structure of Bruton's Tyrosine Kinase in complex with a substituted Cinnoline [[Category...

OCA — Wed, 13 May 2015 11:06:37 GMT

New page: '''Unreleased structure''' The entry 4zlz is ON HOLD Authors: Dougan, D.R. Description: Crystal Structure of Bruton's Tyrosine Kinase in complex with a substituted Cinnoline [[Category...

New page

'''Unreleased structure'''

The entry 4zlz is ON HOLD

Authors: Dougan, D.R.

Description: Crystal Structure of Bruton's Tyrosine Kinase in complex with a substituted Cinnoline
[[Category: Unreleased Structures]]
[[Category: Dougan, D.R]]