3t9t - Revision history

OCA at 12:14, 6 March 2024

2024-03-06T12:14:19Z

←Older revision		Revision as of 12:14, 6 March 2024
Line 3:		Line 3:
	<StructureSection load='3t9t' size='340' side='right'caption='[[3t9t]], [[Resolution\|resolution]] 1.65Å' scene=''>		<StructureSection load='3t9t' size='340' side='right'caption='[[3t9t]], [[Resolution\|resolution]] 1.65Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3t9t]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3T9T OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3T9T FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3t9t]] 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=3T9T OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3T9T FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IAQ:(2Z)-4-(DIMETHYLAMINO)-N-{7-FLUORO-4-[(2-METHYLPHENYL)AMINO]IMIDAZO[1,5-A]QUINOXALIN-8-YL}-N-METHYLBUT-2-ENAMIDE'>IAQ</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]] 1.65Å</td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">ITK, EMT, LYK ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IAQ:(2Z)-4-(DIMETHYLAMINO)-N-{7-FLUORO-4-[(2-METHYLPHENYL)AMINO]IMIDAZO[1,5-A]QUINOXALIN-8-YL}-N-METHYLBUT-2-ENAMIDE'>IAQ</scene></td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </span></td></tr>	+
	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3t9t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3t9t OCA], [https://pdbe.org/3t9t PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3t9t RCSB], [https://www.ebi.ac.uk/pdbsum/3t9t PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3t9t 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=3t9t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3t9t OCA], [https://pdbe.org/3t9t PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3t9t RCSB], [https://www.ebi.ac.uk/pdbsum/3t9t PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3t9t ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
-	[[https://www.uniprot.org/uniprot/ITK_HUMAN ITK_HUMAN]] Defects in ITK are the cause of lymphoproliferative syndrome EBV-associated autosomal type 1 (LPSA1) [MIM:[https://omim.org/entry/613011 613011]]. LPSA1 is a rare immunodeficiency characterized by extreme susceptibility to infection with Epstein-Barr virus (EBV). Inadequate immune response to EBV can have a fatal outcome. Clinical features include splenomegaly, lymphadenopathy, anemia, thrombocytopenia, pancytopenia, recurrent infections. There is an increased risk for lymphoma.<ref>PMID:19425169</ref>	+	[https://www.uniprot.org/uniprot/ITK_HUMAN ITK_HUMAN] Defects in ITK are the cause of lymphoproliferative syndrome EBV-associated autosomal type 1 (LPSA1) [MIM:[https://omim.org/entry/613011 613011]. LPSA1 is a rare immunodeficiency characterized by extreme susceptibility to infection with Epstein-Barr virus (EBV). Inadequate immune response to EBV can have a fatal outcome. Clinical features include splenomegaly, lymphadenopathy, anemia, thrombocytopenia, pancytopenia, recurrent infections. There is an increased risk for lymphoma.<ref>PMID:19425169</ref>
	== Function ==		== Function ==
-	[[https://www.uniprot.org/uniprot/ITK_HUMAN ITK_HUMAN]] Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T-cells and nonconventional NKT-cells. When antigen presenting cells (APC) activate T-cell receptor (TCR), a series of phosphorylation lead to the recruitment of ITK to the cell membrane, in the vicinity of the stimulated TCR receptor, where it is phosphorylated by LCK. Phosphorylation leads to ITK autophosphorylation and full activation. Once activated, phosphorylates PLCG1, leading to the activation of this lipase and subsequent cleavage of its substrates. In turn, the endoplasmic reticulum releases calcium in the cytoplasm and the nuclear activator of activated T-cells (NFAT) translocates into the nucleus to perform its transcriptional duty. Phosphorylates 2 essential adapter proteins: the linker for activation of T-cells/LAT protein and LCP2. Then, a large number of signaling molecules such as VAV1 are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation.<ref>PMID:12186560</ref> <ref>PMID:12682224</ref> <ref>PMID:21725281</ref>	+	[https://www.uniprot.org/uniprot/ITK_HUMAN ITK_HUMAN] Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T-cells and nonconventional NKT-cells. When antigen presenting cells (APC) activate T-cell receptor (TCR), a series of phosphorylation lead to the recruitment of ITK to the cell membrane, in the vicinity of the stimulated TCR receptor, where it is phosphorylated by LCK. Phosphorylation leads to ITK autophosphorylation and full activation. Once activated, phosphorylates PLCG1, leading to the activation of this lipase and subsequent cleavage of its substrates. In turn, the endoplasmic reticulum releases calcium in the cytoplasm and the nuclear activator of activated T-cells (NFAT) translocates into the nucleus to perform its transcriptional duty. Phosphorylates 2 essential adapter proteins: the linker for activation of T-cells/LAT protein and LCP2. Then, a large number of signaling molecules such as VAV1 are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation.<ref>PMID:12186560</ref> <ref>PMID:12682224</ref> <ref>PMID:21725281</ref>
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	Imidazo[1,5-a]quinoxalines were synthesized that function as irreversible Bruton's tyrosine kinase (BTK) inhibitors. The syntheses and SAR of this series of compounds are presented as well as the X-ray crystal structure of the lead compound 36 in complex with a gate-keeper variant of ITK enzyme. The lead compound showed good in vivo efficacy in preclinical RA models.	+
-		+
-	Imidazo[1,5-a]quinoxalines as irreversible BTK inhibitors for the treatment of rheumatoid arthritis.,Kim KH, Maderna A, Schnute ME, Hegen M, Mohan S, Miyashiro J, Lin L, Li E, Keegan S, Lussier J, Wrocklage C, Nickerson-Nutter CL, Wittwer AJ, Soutter H, Caspers N, Han S, Kurumbail R, Dunussi-Joannopoulos K, Douhan J 3rd, Wissner A Bioorg Med Chem Lett. 2011 Nov 1;21(21):6258-63. Epub 2011 Sep 10. PMID:21958547<ref>PMID:21958547</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 3t9t" style="background-color:#fffaf0;"></div~~>	+

	==See Also==		==See Also==
Line 29:		Line 19:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Non-specific protein-tyrosine kinase]]~~	+	[[Category: Caspers N]]
-	[[Category: Caspers, N]]	+	[[Category: Han S]]
-	[[Category: Han, S]]	+
-	~~[[Category: Alpha/beta]]~~	+
-	~~[[Category: Atp binding]]~~	+
-	~~[[Category: Intracellular]]~~	+
-	~~[[Category: Kinase domain]]~~	+
-	~~[[Category: Phosphorylation]]~~	+
-	~~[[Category: Transferase-transferase inhibitor complex~~]]	+

OCA at 16:49, 6 July 2022

2022-07-06T16:49:01Z

←Older revision		Revision as of 16:49, 6 July 2022
Line 1:		Line 1:

	==Crystal structure of BTK mutant (F435T,K596R) complexed with Imidazo[1,5-a]quinoxaline==		==Crystal structure of BTK mutant (F435T,K596R) complexed with Imidazo[1,5-a]quinoxaline==
-	<StructureSection load='3t9t' size='340' side='right' caption='[[3t9t]], [[Resolution\|resolution]] 1.65Å' scene=''>	+	<StructureSection load='3t9t' size='340' side='right'caption='[[3t9t]], [[Resolution\|resolution]] 1.65Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3t9t]] 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=3T9T OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=3T9T FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3t9t]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3T9T OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3T9T FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IAQ:(2Z)-4-(DIMETHYLAMINO)-N-{7-FLUORO-4-[(2-METHYLPHENYL)AMINO]IMIDAZO[1,5-A]QUINOXALIN-8-YL}-N-METHYLBUT-2-ENAMIDE'>IAQ</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IAQ:(2Z)-4-(DIMETHYLAMINO)-N-{7-FLUORO-4-[(2-METHYLPHENYL)AMINO]IMIDAZO[1,5-A]QUINOXALIN-8-YL}-N-METHYLBUT-2-ENAMIDE'>IAQ</scene></td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">ITK, EMT, LYK ([~~http~~://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">ITK, EMT, LYK ([https://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'>[https://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [https://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=3t9t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3t9t OCA], [~~http~~://pdbe.org/3t9t PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=3t9t RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/3t9t PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=3t9t 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=3t9t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3t9t OCA], [https://pdbe.org/3t9t PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3t9t RCSB], [https://www.ebi.ac.uk/pdbsum/3t9t PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3t9t ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
-	[[~~http~~://www.uniprot.org/uniprot/ITK_HUMAN ITK_HUMAN]] Defects in ITK are the cause of lymphoproliferative syndrome EBV-associated autosomal type 1 (LPSA1) [MIM:[~~http~~://omim.org/entry/613011 613011]]. LPSA1 is a rare immunodeficiency characterized by extreme susceptibility to infection with Epstein-Barr virus (EBV). Inadequate immune response to EBV can have a fatal outcome. Clinical features include splenomegaly, lymphadenopathy, anemia, thrombocytopenia, pancytopenia, recurrent infections. There is an increased risk for lymphoma.<ref>PMID:19425169</ref>	+	[[https://www.uniprot.org/uniprot/ITK_HUMAN ITK_HUMAN]] Defects in ITK are the cause of lymphoproliferative syndrome EBV-associated autosomal type 1 (LPSA1) [MIM:[https://omim.org/entry/613011 613011]]. LPSA1 is a rare immunodeficiency characterized by extreme susceptibility to infection with Epstein-Barr virus (EBV). Inadequate immune response to EBV can have a fatal outcome. Clinical features include splenomegaly, lymphadenopathy, anemia, thrombocytopenia, pancytopenia, recurrent infections. There is an increased risk for lymphoma.<ref>PMID:19425169</ref>
	== Function ==		== Function ==
-	[[~~http~~://www.uniprot.org/uniprot/ITK_HUMAN ITK_HUMAN]] Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T-cells and nonconventional NKT-cells. When antigen presenting cells (APC) activate T-cell receptor (TCR), a series of phosphorylation lead to the recruitment of ITK to the cell membrane, in the vicinity of the stimulated TCR receptor, where it is phosphorylated by LCK. Phosphorylation leads to ITK autophosphorylation and full activation. Once activated, phosphorylates PLCG1, leading to the activation of this lipase and subsequent cleavage of its substrates. In turn, the endoplasmic reticulum releases calcium in the cytoplasm and the nuclear activator of activated T-cells (NFAT) translocates into the nucleus to perform its transcriptional duty. Phosphorylates 2 essential adapter proteins: the linker for activation of T-cells/LAT protein and LCP2. Then, a large number of signaling molecules such as VAV1 are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation.<ref>PMID:12186560</ref> <ref>PMID:12682224</ref> <ref>PMID:21725281</ref>	+	[[https://www.uniprot.org/uniprot/ITK_HUMAN ITK_HUMAN]] Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T-cells and nonconventional NKT-cells. When antigen presenting cells (APC) activate T-cell receptor (TCR), a series of phosphorylation lead to the recruitment of ITK to the cell membrane, in the vicinity of the stimulated TCR receptor, where it is phosphorylated by LCK. Phosphorylation leads to ITK autophosphorylation and full activation. Once activated, phosphorylates PLCG1, leading to the activation of this lipase and subsequent cleavage of its substrates. In turn, the endoplasmic reticulum releases calcium in the cytoplasm and the nuclear activator of activated T-cells (NFAT) translocates into the nucleus to perform its transcriptional duty. Phosphorylates 2 essential adapter proteins: the linker for activation of T-cells/LAT protein and LCP2. Then, a large number of signaling molecules such as VAV1 are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation.<ref>PMID:12186560</ref> <ref>PMID:12682224</ref> <ref>PMID:21725281</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 24:		Line 24:

	==See Also==		==See Also==
-	*[[Tyrosine kinase\|Tyrosine kinase]]	+	*[[Tyrosine kinase 3D structures\|Tyrosine kinase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
Line 30:		Line 30:
	</StructureSection>		</StructureSection>
	[[Category: Human]]		[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Non-specific protein-tyrosine kinase]]		[[Category: Non-specific protein-tyrosine kinase]]
	[[Category: Caspers, N]]		[[Category: Caspers, N]]

OCA at 17:58, 4 August 2016

2016-08-04T17:58:18Z

←Older revision		Revision as of 17:58, 4 August 2016
Line 1:		Line 1:
		+
	==Crystal structure of BTK mutant (F435T,K596R) complexed with Imidazo[1,5-a]quinoxaline==		==Crystal structure of BTK mutant (F435T,K596R) complexed with Imidazo[1,5-a]quinoxaline==
	<StructureSection load='3t9t' size='340' side='right' caption='[[3t9t]], [[Resolution\|resolution]] 1.65Å' scene=''>		<StructureSection load='3t9t' size='340' side='right' caption='[[3t9t]], [[Resolution\|resolution]] 1.65Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3t9t]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/~~Homo_sapiens Homo sapiens~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3T9T OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3T9T FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3t9t]] 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=3T9T OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3T9T FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IAQ:(2Z)-4-(DIMETHYLAMINO)-N-{7-FLUORO-4-[(2-METHYLPHENYL)AMINO]IMIDAZO[1,5-A]QUINOXALIN-8-YL}-N-METHYLBUT-2-ENAMIDE'>IAQ</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IAQ:(2Z)-4-(DIMETHYLAMINO)-N-{7-FLUORO-4-[(2-METHYLPHENYL)AMINO]IMIDAZO[1,5-A]QUINOXALIN-8-YL}-N-METHYLBUT-2-ENAMIDE'>IAQ</scene></td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">ITK, EMT, LYK ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 ~~Homo sapiens~~])</td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">ITK, EMT, LYK ([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=3t9t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3t9t OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3t9t RCSB], [http://www.ebi.ac.uk/pdbsum/3t9t 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=3t9t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3t9t OCA], [http://pdbe.org/3t9t PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3t9t RCSB], [http://www.ebi.ac.uk/pdbsum/3t9t PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3t9t 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 3t9t" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
Line 27:		Line 29:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Homo sapiens~~]]	+	[[Category: Human]]
	[[Category: Non-specific protein-tyrosine kinase]]		[[Category: Non-specific protein-tyrosine kinase]]
	[[Category: Caspers, N]]		[[Category: Caspers, N]]

OCA at 06:30, 21 December 2014

2014-12-21T06:30:23Z

←Older revision		Revision as of 06:30, 21 December 2014
Line 1:		Line 1:
-	~~{{STRUCTURE_3t9t\| PDB=3t9t \| SCENE= }}~~	+	==Crystal structure of BTK mutant (F435T,K596R) complexed with Imidazo[1,5-a]quinoxaline==
-	===Crystal structure of BTK mutant (F435T,K596R) complexed with Imidazo[1,5-a]quinoxaline===	+	<StructureSection load='3t9t' size='340' side='right' caption='[[3t9t]], [[Resolution\|resolution]] 1.65Å' scene=''>
-	{~~{ABSTRACT_PUBMED_21958547}~~}	+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[3t9t]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3T9T OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3T9T FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IAQ:(2Z)-4-(DIMETHYLAMINO)-N-{7-FLUORO-4-[(2-METHYLPHENYL)AMINO]IMIDAZO[1,5-A]QUINOXALIN-8-YL}-N-METHYLBUT-2-ENAMIDE'>IAQ</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">ITK, EMT, LYK ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=3t9t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3t9t OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3t9t RCSB], [http://www.ebi.ac.uk/pdbsum/3t9t PDBsum]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/ITK_HUMAN ITK_HUMAN]] Defects in ITK are the cause of lymphoproliferative syndrome EBV-associated autosomal type 1 (LPSA1) [MIM:[http://omim.org/entry/613011 613011]]. LPSA1 is a rare immunodeficiency characterized by extreme susceptibility to infection with Epstein-Barr virus (EBV). Inadequate immune response to EBV can have a fatal outcome. Clinical features include splenomegaly, lymphadenopathy, anemia, thrombocytopenia, pancytopenia, recurrent infections. There is an increased risk for lymphoma.<ref>PMID:19425169</ref>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/ITK_HUMAN ITK_HUMAN]] Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T-cells and nonconventional NKT-cells. When antigen presenting cells (APC) activate T-cell receptor (TCR), a series of phosphorylation lead to the recruitment of ITK to the cell membrane, in the vicinity of the stimulated TCR receptor, where it is phosphorylated by LCK. Phosphorylation leads to ITK autophosphorylation and full activation. Once activated, phosphorylates PLCG1, leading to the activation of this lipase and subsequent cleavage of its substrates. In turn, the endoplasmic reticulum releases calcium in the cytoplasm and the nuclear activator of activated T-cells (NFAT) translocates into the nucleus to perform its transcriptional duty. Phosphorylates 2 essential adapter proteins: the linker for activation of T-cells/LAT protein and LCP2. Then, a large number of signaling molecules such as VAV1 are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation.<ref>PMID:12186560</ref> <ref>PMID:12682224</ref> <ref>PMID:21725281</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Imidazo[1,5-a]quinoxalines were synthesized that function as irreversible Bruton's tyrosine kinase (BTK) inhibitors. The syntheses and SAR of this series of compounds are presented as well as the X-ray crystal structure of the lead compound 36 in complex with a gate-keeper variant of ITK enzyme. The lead compound showed good in vivo efficacy in preclinical RA models.

-	~~==Disease==~~	+	Imidazo[1,5-a]quinoxalines as irreversible BTK inhibitors for the treatment of rheumatoid arthritis.,Kim KH, Maderna A, Schnute ME, Hegen M, Mohan S, Miyashiro J, Lin L, Li E, Keegan S, Lussier J, Wrocklage C, Nickerson-Nutter CL, Wittwer AJ, Soutter H, Caspers N, Han S, Kurumbail R, Dunussi-Joannopoulos K, Douhan J 3rd, Wissner A Bioorg Med Chem Lett. 2011 Nov 1;21(21):6258-63. Epub 2011 Sep 10. PMID:21958547<ref>PMID:21958547</ref>
-	[~~[http://www.uniprot.org/uniprot/ITK_HUMAN ITK_HUMAN~~]~~] Defects in ITK are~~ the ~~cause~~ of ~~lymphoproliferative syndrome EBV-associated autosomal type 1 (LPSA1) [MIM:[http://omim~~.~~org/entry/613011 613011]]. LPSA1 is a rare immunodeficiency characterized by extreme susceptibility to infection with Epstein~~-~~Barr virus (EBV). Inadequate immune response to EBV can have a fatal outcome. Clinical features include splenomegaly~~, ~~lymphadenopathy~~, ~~anemia~~, ~~thrombocytopenia~~, ~~pancytopenia~~, ~~recurrent infections~~. ~~There is an increased risk for lymphoma~~.<ref>PMID:~~19425169~~</ref>	+

-	~~==Function==~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[http:~~//www.uniprot.org/uniprot/ITK_HUMAN ITK_HUMAN]] Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T-cells and nonconventional NKT-cells. When antigen presenting cells (APC) activate T-cell receptor (TCR), a ~~series~~ of ~~phosphorylation lead to~~ the ~~recruitment of ITK to the cell membrane, in the vicinity of the stimulated TCR receptor, where it is phosphorylated by LCK~~. ~~Phosphorylation leads to ITK autophosphorylation and full activation~~. ~~Once activated, phosphorylates PLCG1, leading to the activation~~ of this lipase and subsequent cleavage of its substrates. In turn, the endoplasmic reticulum releases calcium in the cytoplasm and the nuclear activator of activated T-cells (NFAT) translocates into the nucleus to perform its transcriptional duty. Phosphorylates 2 essential adapter proteins: the linker for activation of T-cells/LAT protein and LCP2. Then, a large number of signaling molecules such as VAV1 are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation.<~~ref~~>~~PMID:12186560~~</~~ref~~>~~<ref>PMID:12682224</ref><ref>PMID:21725281</ref>~~	+	</div>
-		+
-	~~==About this Structure==~~	+
-	[[3t9t]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3T9T OCA].	+

	==See Also==		==See Also==
	*[[Tyrosine kinase\|Tyrosine kinase]]		*[[Tyrosine kinase\|Tyrosine kinase]]
-		+	== References ==
-	==~~Reference~~==	+	<references/>
-	~~<ref group="xtra">PMID:021958547</ref>~~<references ~~group="xtra"~~/><~~references~~/>	+	__TOC__
		+	</StructureSection>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Non-specific protein-tyrosine kinase]]		[[Category: Non-specific protein-tyrosine kinase]]
-	[[Category: Caspers, N.]]	+	[[Category: Caspers, N]]
-	[[Category: Han, S.]]	+	[[Category: Han, S]]
	[[Category: Alpha/beta]]		[[Category: Alpha/beta]]
	[[Category: Atp binding]]		[[Category: Atp binding]]

OCA at 23:45, 24 March 2013

2013-03-24T23:45:48Z

←Older revision		Revision as of 23:45, 24 March 2013
Line 1:		Line 1:
-	[[Image:3t9t.png\|left\|200px]]
-
	{{STRUCTURE_3t9t\| PDB=3t9t \| SCENE= }}		{{STRUCTURE_3t9t\| PDB=3t9t \| SCENE= }}
-
	===Crystal structure of BTK mutant (F435T,K596R) complexed with Imidazo[1,5-a]quinoxaline===		===Crystal structure of BTK mutant (F435T,K596R) complexed with Imidazo[1,5-a]quinoxaline===
		+	{{ABSTRACT_PUBMED_21958547}}

-	~~{{ABSTRACT_PUBMED_21958547}}~~	+	==Disease==
		+	[[http://www.uniprot.org/uniprot/ITK_HUMAN ITK_HUMAN]] Defects in ITK are the cause of lymphoproliferative syndrome EBV-associated autosomal type 1 (LPSA1) [MIM:[http://omim.org/entry/613011 613011]]. LPSA1 is a rare immunodeficiency characterized by extreme susceptibility to infection with Epstein-Barr virus (EBV). Inadequate immune response to EBV can have a fatal outcome. Clinical features include splenomegaly, lymphadenopathy, anemia, thrombocytopenia, pancytopenia, recurrent infections. There is an increased risk for lymphoma.<ref>PMID:19425169</ref>
		+
		+	==Function==
		+	[[http://www.uniprot.org/uniprot/ITK_HUMAN ITK_HUMAN]] Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T-cells and nonconventional NKT-cells. When antigen presenting cells (APC) activate T-cell receptor (TCR), a series of phosphorylation lead to the recruitment of ITK to the cell membrane, in the vicinity of the stimulated TCR receptor, where it is phosphorylated by LCK. Phosphorylation leads to ITK autophosphorylation and full activation. Once activated, phosphorylates PLCG1, leading to the activation of this lipase and subsequent cleavage of its substrates. In turn, the endoplasmic reticulum releases calcium in the cytoplasm and the nuclear activator of activated T-cells (NFAT) translocates into the nucleus to perform its transcriptional duty. Phosphorylates 2 essential adapter proteins: the linker for activation of T-cells/LAT protein and LCP2. Then, a large number of signaling molecules such as VAV1 are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation.<ref>PMID:12186560</ref><ref>PMID:12682224</ref><ref>PMID:21725281</ref>

	==About this Structure==		==About this Structure==
Line 14:		Line 16:

	==Reference==		==Reference==
-	<ref group="xtra">PMID:021958547</ref><references group="xtra"/>	+	<ref group="xtra">PMID:021958547</ref><references group="xtra"/><references/>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Non-specific protein-tyrosine kinase]]		[[Category: Non-specific protein-tyrosine kinase]]

OCA at 07:43, 20 October 2012

2012-10-20T07:43:11Z

←Older revision		Revision as of 07:43, 20 October 2012
Line 8:		Line 8:

	==About this Structure==		==About this Structure==
-	[[3t9t]] is a 1 chain structure ~~of [[Tyrosine kinase]]~~ with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3T9T OCA].	+	[[3t9t]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3T9T OCA].

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

OCA at 17:13, 25 July 2012

2012-07-25T17:13:53Z

←Older revision		Revision as of 17:13, 25 July 2012
Line 1:		Line 1:
	[[Image:3t9t.png\|left\|200px]]		[[Image:3t9t.png\|left\|200px]]

-	<!--
-	The line below this paragraph, containing "STRUCTURE_3t9t", creates the "Structure Box" on the page.
-	You may change the PDB parameter (which sets the PDB file loaded into the applet)
-	or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
-	or leave the SCENE parameter empty for the default display.
-	-->
	{{STRUCTURE_3t9t\| PDB=3t9t \| SCENE= }}		{{STRUCTURE_3t9t\| PDB=3t9t \| SCENE= }}

	===Crystal structure of BTK mutant (F435T,K596R) complexed with Imidazo[1,5-a]quinoxaline===		===Crystal structure of BTK mutant (F435T,K596R) complexed with Imidazo[1,5-a]quinoxaline===

-
-	<!--
-	The line below this paragraph, {{ABSTRACT_PUBMED_21958547}}, adds the Publication Abstract to the page
-	(as it appears on PubMed at http://www.pubmed.gov), where 21958547 is the PubMed ID number.
-	-->
	{{ABSTRACT_PUBMED_21958547}}		{{ABSTRACT_PUBMED_21958547}}

	==About this Structure==		==About this Structure==
-	[[3t9t]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3T9T OCA].	+	[[3t9t]] is a 1 chain structure of [[Tyrosine kinase]] with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3T9T OCA].
		+
		+	==See Also==
		+	*[[Tyrosine kinase\|Tyrosine kinase]]

	==Reference==		==Reference==

OCA at 07:07, 30 October 2011

2011-10-30T07:07:48Z

←Older revision		Revision as of 07:07, 30 October 2011
Line 1:		Line 1:
-	~~'''Unreleased structure'''~~	+	[[Image:3t9t.png\|left\|200px]]

-	The ~~entry 3t9t~~ is ~~ON HOLD~~ ~~until Paper Publication~~	+	<!--
		+	The line below this paragraph, containing "STRUCTURE_3t9t", creates the "Structure Box" on the page.
		+	You may change the PDB parameter (which sets the PDB file loaded into the applet)
		+	or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
		+	or leave the SCENE parameter empty for the default display.
		+	-->
		+	{{STRUCTURE_3t9t\| PDB=3t9t \| SCENE= }}

-	~~Authors: Han~~, S., ~~Caspers, N.~~	+	===Crystal structure of BTK mutant (F435T,K596R) complexed with Imidazo[1,5-a]quinoxaline===

-	~~Description: Crystal structure of BTK mutant (F435T~~,~~K596R~~) ~~complexed with Imidazo~~[1,5-a]~~quinoxaline~~	+
		+	<!--
		+	The line below this paragraph, {{ABSTRACT_PUBMED_21958547}}, adds the Publication Abstract to the page
		+	(as it appears on PubMed at http://www.pubmed.gov), where 21958547 is the PubMed ID number.
		+	-->
		+	{{ABSTRACT_PUBMED_21958547}}
		+
		+	==About this Structure==
		+	[[3t9t]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3T9T OCA].
		+
		+	==Reference==
		+	<ref group="xtra">PMID:021958547</ref><references group="xtra"/>
		+	[[Category: Homo sapiens]]
		+	[[Category: Non-specific protein-tyrosine kinase]]
		+	[[Category: Caspers, N.]]
		+	[[Category: Han, S.]]
		+	[[Category: Alpha/beta]]
		+	[[Category: Atp binding]]
		+	[[Category: Intracellular]]
		+	[[Category: Kinase domain]]
		+	[[Category: Phosphorylation]]
		+	[[Category: Transferase-transferase inhibitor complex]]

OCA at 06:02, 14 September 2011

2011-09-14T06:02:31Z

←Older revision		Revision as of 06:02, 14 September 2011
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 3t9t is ON HOLD	+	The entry 3t9t is ON HOLD until Paper Publication

	Authors: Han, S., Caspers, N.		Authors: Han, S., Caspers, N.

	Description: Crystal structure of BTK mutant (F435T,K596R) complexed with Imidazo[1,5-a]quinoxaline		Description: Crystal structure of BTK mutant (F435T,K596R) complexed with Imidazo[1,5-a]quinoxaline

OCA: Protected "3t9t" [edit=sysop:move=sysop]

2011-08-10T05:38:32Z

Protected "3t9t" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:38, 10 August 2011