3qgy - Revision history

OCA at 08:35, 20 March 2024

OCA — Wed, 20 Mar 2024 08:35:14 GMT

←Older revision		Revision as of 08:35, 20 March 2024
Line 3:		Line 3:
	<StructureSection load='3qgy' size='340' side='right'caption='[[3qgy]], [[Resolution\|resolution]] 2.10Å' scene=''>		<StructureSection load='3qgy' size='340' side='right'caption='[[3qgy]], [[Resolution\|resolution]] 2.10Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3qgy]] is a 2 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=3QGY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3QGY FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3qgy]] is a 2 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=3QGY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3QGY FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=L7O:N-{5-[2-(METHYLAMINO)PYRIMIDIN-4-YL]-2-OXO-1,2-DIHYDROPYRIDIN-3-YL}-4-(PIPERIDIN-1-YL)BENZAMIDE'>L7O</scene>, <scene name='pdbligand=PQC:3-[(8-PHENYLTHIENO[2,3-H]QUINAZOLIN-2-YL)AMINO]BENZENESULFONAMIDE'>PQC</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]] 2.1Å</td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3qgw\|3qgw]]</div></td></tr>~~	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=L7O:N-{5-[2-(METHYLAMINO)PYRIMIDIN-4-YL]-2-OXO-1,2-DIHYDROPYRIDIN-3-YL}-4-(PIPERIDIN-1-YL)BENZAMIDE'>L7O</scene>, <scene name='pdbligand=PQC:3-[(8-PHENYLTHIENO[2,3-H]QUINAZOLIN-2-YL)AMINO]BENZENESULFONAMIDE'>PQC</scene></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'>[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=3qgy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qgy OCA], [https://pdbe.org/3qgy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3qgy RCSB], [https://www.ebi.ac.uk/pdbsum/3qgy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3qgy 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=3qgy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qgy OCA], [https://pdbe.org/3qgy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3qgy RCSB], [https://www.ebi.ac.uk/pdbsum/3qgy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3qgy 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 ==~~	+
-	Interleukin-2 inducible T-cell kinase (Itk) plays a role in T-cell functions, and its inhibition potentially represents an attractive intervention point to treat autoimmune and allergic diseases. Herein we describe the discovery of a series of potent and selective novel inhibitors of Itk. These inhibitors were identified by structure-based design, starting from a fragment generated de novo, the 3-aminopyrid-2-one motif. Functionalization of the 3-amino group enabled rapid enhancement of the inhibitory activity against Itk, while introduction of a substituted heteroaromatic ring in position 5 of the pyridone fragment was key to achieving optimal selectivity over related kinases. A careful analysis of the hydration patterns in the kinase active site was necessary to fully explain the observed selectivity profile. The best molecule prepared in this optimization campaign, 7v, inhibits Itk with a K(i) of 7 nM and has a good selectivity profile across kinases.	+
-		+
-	Discovery and structure-activity relationship of 3-aminopyrid-2-ones as potent and selective interleukin-2 inducible T-cell kinase (Itk) inhibitors.,Charrier JD, Miller A, Kay DP, Brenchley G, Twin HC, Collier PN, Ramaya S, Keily SB, Durrant SJ, Knegtel RM, Tanner AJ, Brown K, Curnock AP, Jimenez JM J Med Chem. 2011 Apr 14;54(7):2341-50. Epub 2011 Mar 10. PMID:21391610<ref>PMID:21391610</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 3qgy" style="background-color:#fffaf0;"></div~~>	+

	==See Also==		==See Also==
Line 30:		Line 19:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Non-specific protein-tyrosine kinase]]~~	+	[[Category: Brown K]]
-	[[Category: Brown, K]]	+	[[Category: Cheetham GMT]]
-	[[Category: Cheetham~~, G M.T]]~~	+
-	~~[[Category: Protein kinase]]~~	+
-	~~[[Category: Transferase-transferase inhibitor complex~~]]	+

OCA at 06:08, 8 June 2022

OCA — Wed, 08 Jun 2022 06:08:34 GMT

←Older revision		Revision as of 06:08, 8 June 2022
Line 1:		Line 1:

	==Crystal structure of ITK inhibitor complex==		==Crystal structure of ITK inhibitor complex==
-	<StructureSection load='3qgy' size='340' side='right' caption='[[3qgy]], [[Resolution\|resolution]] 2.10Å' scene=''>	+	<StructureSection load='3qgy' size='340' side='right'caption='[[3qgy]], [[Resolution\|resolution]] 2.10Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3qgy]] is a 2 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=3QGY OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=3QGY FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3qgy]] is a 2 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=3QGY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3QGY FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=L7O:N-{5-[2-(METHYLAMINO)PYRIMIDIN-4-YL]-2-OXO-1,2-DIHYDROPYRIDIN-3-YL}-4-(PIPERIDIN-1-YL)BENZAMIDE'>L7O</scene>, <scene name='pdbligand=PQC:3-[(8-PHENYLTHIENO[2,3-H]QUINAZOLIN-2-YL)AMINO]BENZENESULFONAMIDE'>PQC</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=L7O:N-{5-[2-(METHYLAMINO)PYRIMIDIN-4-YL]-2-OXO-1,2-DIHYDROPYRIDIN-3-YL}-4-(PIPERIDIN-1-YL)BENZAMIDE'>L7O</scene>, <scene name='pdbligand=PQC:3-[(8-PHENYLTHIENO[2,3-H]QUINAZOLIN-2-YL)AMINO]BENZENESULFONAMIDE'>PQC</scene></td></tr>
-	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3qgw\|3qgw]]</td></tr>	+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3qgw\|3qgw]]</div></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=3qgy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qgy OCA], [~~http~~://pdbe.org/3qgy PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=3qgy RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/3qgy PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=3qgy 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=3qgy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qgy OCA], [https://pdbe.org/3qgy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3qgy RCSB], [https://www.ebi.ac.uk/pdbsum/3qgy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3qgy 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 25:		Line 25:

	==See Also==		==See Also==
-	*[[Tyrosine kinase\|Tyrosine kinase]]	+	*[[Tyrosine kinase 3D structures\|Tyrosine kinase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
Line 31:		Line 31:
	</StructureSection>		</StructureSection>
	[[Category: Human]]		[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Non-specific protein-tyrosine kinase]]		[[Category: Non-specific protein-tyrosine kinase]]
	[[Category: Brown, K]]		[[Category: Brown, K]]

OCA at 17:00, 5 August 2016

OCA — Fri, 05 Aug 2016 17:00:47 GMT

←Older revision		Revision as of 17:00, 5 August 2016
Line 1:		Line 1:
		+
	==Crystal structure of ITK inhibitor complex==		==Crystal structure of ITK inhibitor complex==
	<StructureSection load='3qgy' size='340' side='right' caption='[[3qgy]], [[Resolution\|resolution]] 2.10Å' scene=''>		<StructureSection load='3qgy' size='340' side='right' caption='[[3qgy]], [[Resolution\|resolution]] 2.10Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3qgy]] is a 2 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=3QGY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3QGY FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3qgy]] is a 2 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=3QGY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3QGY FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=L7O:N-{5-[2-(METHYLAMINO)PYRIMIDIN-4-YL]-2-OXO-1,2-DIHYDROPYRIDIN-3-YL}-4-(PIPERIDIN-1-YL)BENZAMIDE'>L7O</scene>, <scene name='pdbligand=PQC:3-[(8-PHENYLTHIENO[2,3-H]QUINAZOLIN-2-YL)AMINO]BENZENESULFONAMIDE'>PQC</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=L7O:N-{5-[2-(METHYLAMINO)PYRIMIDIN-4-YL]-2-OXO-1,2-DIHYDROPYRIDIN-3-YL}-4-(PIPERIDIN-1-YL)BENZAMIDE'>L7O</scene>, <scene name='pdbligand=PQC:3-[(8-PHENYLTHIENO[2,3-H]QUINAZOLIN-2-YL)AMINO]BENZENESULFONAMIDE'>PQC</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3qgw\|3qgw]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3qgw\|3qgw]]</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=3qgy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qgy OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3qgy RCSB], [http://www.ebi.ac.uk/pdbsum/3qgy 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=3qgy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qgy OCA], [http://pdbe.org/3qgy PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3qgy RCSB], [http://www.ebi.ac.uk/pdbsum/3qgy PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3qgy ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 21:		Line 22:
	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 3qgy" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
Line 28:		Line 30:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Homo sapiens~~]]	+	[[Category: Human]]
	[[Category: Non-specific protein-tyrosine kinase]]		[[Category: Non-specific protein-tyrosine kinase]]
	[[Category: Brown, K]]		[[Category: Brown, K]]

OCA at 10:14, 19 December 2014

OCA — Fri, 19 Dec 2014 10:14:22 GMT

←Older revision		Revision as of 10:14, 19 December 2014
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-	~~{{STRUCTURE_3qgy~~\| ~~PDB~~=3qgy \| ~~SCENE~~= }}	+	==Crystal structure of ITK inhibitor complex==
-	===~~Crystal structure~~ of ITK ~~inhibitor complex~~===	+	<StructureSection load='3qgy' size='340' side='right' caption='[[3qgy]], [[Resolution\|resolution]] 2.10Å' scene=''>
-	~~{{ABSTRACT_PUBMED_21391610}}~~	+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[3qgy]] is a 2 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=3QGY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3QGY FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=L7O:N-{5-[2-(METHYLAMINO)PYRIMIDIN-4-YL]-2-OXO-1,2-DIHYDROPYRIDIN-3-YL}-4-(PIPERIDIN-1-YL)BENZAMIDE'>L7O</scene>, <scene name='pdbligand=PQC:3-[(8-PHENYLTHIENO[2,3-H]QUINAZOLIN-2-YL)AMINO]BENZENESULFONAMIDE'>PQC</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3qgw\|3qgw]]</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=3qgy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qgy OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3qgy RCSB], [http://www.ebi.ac.uk/pdbsum/3qgy 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 ==
		+	Interleukin-2 inducible T-cell kinase (Itk) plays a role in T-cell functions, and its inhibition potentially represents an attractive intervention point to treat autoimmune and allergic diseases. Herein we describe the discovery of a series of potent and selective novel inhibitors of Itk. These inhibitors were identified by structure-based design, starting from a fragment generated de novo, the 3-aminopyrid-2-one motif. Functionalization of the 3-amino group enabled rapid enhancement of the inhibitory activity against Itk, while introduction of a substituted heteroaromatic ring in position 5 of the pyridone fragment was key to achieving optimal selectivity over related kinases. A careful analysis of the hydration patterns in the kinase active site was necessary to fully explain the observed selectivity profile. The best molecule prepared in this optimization campaign, 7v, inhibits Itk with a K(i) of 7 nM and has a good selectivity profile across kinases.

-	~~==Disease==~~	+	Discovery and structure-activity relationship of 3-aminopyrid-2-ones as potent and selective interleukin-2 inducible T-cell kinase (Itk) inhibitors.,Charrier JD, Miller A, Kay DP, Brenchley G, Twin HC, Collier PN, Ramaya S, Keily SB, Durrant SJ, Knegtel RM, Tanner AJ, Brown K, Curnock AP, Jimenez JM J Med Chem. 2011 Apr 14;54(7):2341-50. Epub 2011 Mar 10. PMID:21391610<ref>PMID:21391610</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~~==	+	==See Also==
-	[[~~3qgy~~]] is a 2 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=3QGY OCA].	+	*[[Tyrosine kinase\|Tyrosine kinase]]
-		+	== References ==
-	==~~Reference~~==	+	<references/>
-	~~<ref group="xtra">PMID:021391610</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: Brown, K.]]	+	[[Category: Brown, K]]
-	[[Category: Cheetham, G M.T.]]	+	[[Category: Cheetham, G M.T]]
	[[Category: Protein kinase]]		[[Category: Protein kinase]]
	[[Category: Transferase-transferase inhibitor complex]]		[[Category: Transferase-transferase inhibitor complex]]

OCA at 02:06, 25 March 2013

OCA — Mon, 25 Mar 2013 02:06:12 GMT

←Older revision		Revision as of 02:06, 25 March 2013
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-	[[Image:3qgy.jpg\|left\|200px]]
-
-	<!--
-	The line below this paragraph, containing "STRUCTURE_3qgy", 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_3qgy\| PDB=3qgy \| SCENE= }}		{{STRUCTURE_3qgy\| PDB=3qgy \| SCENE= }}
-
	===Crystal structure of ITK inhibitor complex===		===Crystal structure of ITK inhibitor complex===
		+	{{ABSTRACT_PUBMED_21391610}}

		+	==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==
-	~~The line below this paragraph, {{ABSTRACT_PUBMED_21391610}}, adds the Publication Abstract to the page~~	+	[[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>
-	~~(as it appears on PubMed at~~ http://www.~~pubmed~~.~~gov~~), where ~~21391610~~ is the ~~PubMed ID number~~.	+
-	-->	+
-	~~{{ABSTRACT_PUBMED_21391610}}~~	+

	==About this Structure==		==About this Structure==
Line 22:		Line 13:

	==Reference==		==Reference==
-	<ref group="xtra">PMID:021391610</ref><references group="xtra"/>	+	<ref group="xtra">PMID:021391610</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 16:38, 22 June 2011

OCA — Wed, 22 Jun 2011 16:38:18 GMT

←Older revision		Revision as of 16:38, 22 June 2011
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-	~~'''Unreleased structure'''~~	+	[[Image:3qgy.jpg\|left\|200px]]

-	The ~~entry 3qgy~~ is ~~ON HOLD~~	+	<!--
		+	The line below this paragraph, containing "STRUCTURE_3qgy", 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_3qgy\| PDB=3qgy \| SCENE= }}

-	~~Authors: Brown, K., Cheetham, G.M.T.~~	+	===Crystal structure of ITK inhibitor complex===

-	~~Description~~: ~~Crystal~~ structure ~~of ITK~~ inhibitor complex	+
		+	<!--
		+	The line below this paragraph, {{ABSTRACT_PUBMED_21391610}}, adds the Publication Abstract to the page
		+	(as it appears on PubMed at http://www.pubmed.gov), where 21391610 is the PubMed ID number.
		+	-->
		+	{{ABSTRACT_PUBMED_21391610}}
		+
		+	==About this Structure==
		+	[[3qgy]] is a 2 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=3QGY OCA].
		+
		+	==Reference==
		+	<ref group="xtra">PMID:021391610</ref><references group="xtra"/>
		+	[[Category: Homo sapiens]]
		+	[[Category: Non-specific protein-tyrosine kinase]]
		+	[[Category: Brown, K.]]
		+	[[Category: Cheetham, G M.T.]]
		+	[[Category: Protein kinase]]
		+	[[Category: Transferase-transferase inhibitor complex]]

OCA at 05:18, 1 June 2011

OCA — Wed, 01 Jun 2011 05:18:02 GMT

←Older revision		Revision as of 05:18, 1 June 2011
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	Authors: Brown, K., Cheetham, G.M.T.		Authors: Brown, K., Cheetham, G.M.T.

-	Description: Crystal structure of ITK ~~Kinase~~ inhibitor complex	+	Description: Crystal structure of ITK inhibitor complex

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

OCA — Wed, 02 Feb 2011 06:12:20 GMT

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

←Older revision

Revision as of 06:12, 2 February 2011

OCA: New page: '''Unreleased structure''' The entry 3qgy is ON HOLD Authors: Brown, K., Cheetham, G.M.T. Description: Crystal structure of ITK Kinase inhibitor complex

OCA — Wed, 02 Feb 2011 06:12:20 GMT

New page: '''Unreleased structure''' The entry 3qgy is ON HOLD Authors: Brown, K., Cheetham, G.M.T. Description: Crystal structure of ITK Kinase inhibitor complex

New page

'''Unreleased structure'''

The entry 3qgy is ON HOLD

Authors: Brown, K., Cheetham, G.M.T.

Description: Crystal structure of ITK Kinase inhibitor complex