2x7o - Revision history

OCA at 10:25, 20 December 2023

OCA — Wed, 20 Dec 2023 10:25:46 GMT

←Older revision		Revision as of 10:25, 20 December 2023
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[2x7o]] is a 5 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=2X7O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2X7O FirstGlance]. <br>		<table><tr><td colspan='2'>[[2x7o]] is a 5 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=2X7O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2X7O FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZOP:(3Z)-N-ETHYL-N-METHYL-2-OXO-3-(PHENYL{[4-(PIPERIDIN-1-YLMETHYL)PHENYL]AMINO}METHYLIDENE)-2,3-DIHYDRO-1H-INDOLE-6-CARBOXAMIDE'>ZOP</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]] 3.7Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZOP:(3Z)-N-ETHYL-N-METHYL-2-OXO-3-(PHENYL{[4-(PIPERIDIN-1-YLMETHYL)PHENYL]AMINO}METHYLIDENE)-2,3-DIHYDRO-1H-INDOLE-6-CARBOXAMIDE'>ZOP</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=2x7o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2x7o OCA], [https://pdbe.org/2x7o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2x7o RCSB], [https://www.ebi.ac.uk/pdbsum/2x7o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2x7o 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=2x7o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2x7o OCA], [https://pdbe.org/2x7o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2x7o RCSB], [https://www.ebi.ac.uk/pdbsum/2x7o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2x7o ProSAT]</span></td></tr>
	</table>		</table>

OCA at 03:41, 2 October 2022

OCA — Sun, 02 Oct 2022 03:41:14 GMT

←Older revision		Revision as of 03:41, 2 October 2022
Line 3:		Line 3:
	<StructureSection load='2x7o' size='340' side='right'caption='[[2x7o]], [[Resolution\|resolution]] 3.70Å' scene=''>		<StructureSection load='2x7o' size='340' side='right'caption='[[2x7o]], [[Resolution\|resolution]] 3.70Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[2x7o]] is a 5 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=2X7O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2X7O FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[2x7o]] is a 5 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=2X7O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2X7O FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZOP:(3Z)-N-ETHYL-N-METHYL-2-OXO-3-(PHENYL{[4-(PIPERIDIN-1-YLMETHYL)PHENYL]AMINO}METHYLIDENE)-2,3-DIHYDRO-1H-INDOLE-6-CARBOXAMIDE'>ZOP</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZOP:(3Z)-N-ETHYL-N-METHYL-2-OXO-3-(PHENYL{[4-(PIPERIDIN-1-YLMETHYL)PHENYL]AMINO}METHYLIDENE)-2,3-DIHYDRO-1H-INDOLE-6-CARBOXAMIDE'>ZOP</scene></td></tr>
-	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1py5\|1py5]], [[1ias\|1ias]], [[2wou\|2wou]], [[2wot\|2wot]], [[1b6c\|1b6c]], [[1vjy\|1vjy]], [[1rw8\|1rw8]]</div></td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Receptor_protein_serine/threonine_kinase Receptor protein serine/threonine kinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.30 2.7.11.30] </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=2x7o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2x7o OCA], [https://pdbe.org/2x7o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2x7o RCSB], [https://www.ebi.ac.uk/pdbsum/2x7o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2x7o 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=2x7o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2x7o OCA], [https://pdbe.org/2x7o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2x7o RCSB], [https://www.ebi.ac.uk/pdbsum/2x7o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2x7o ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
-	[[https://www.uniprot.org/uniprot/TGFR1_HUMAN TGFR1_HUMAN]] Defects in TGFBR1 are the cause of Loeys-Dietz syndrome type 1A (LDS1A) [MIM:[https://omim.org/entry/609192 609192]]; also known as Furlong syndrome or Loeys-Dietz aortic aneurysm syndrome (LDAS). LDS1 is an aortic aneurysm syndrome with widespread systemic involvement. The disorder is characterized by arterial tortuosity and aneurysms, craniosynostosis, hypertelorism, and bifid uvula or cleft palate. Other findings include exotropy, micrognathia and retrognathia, structural brain abnormalities, intellectual deficit, congenital heart disease, translucent skin, joint hyperlaxity and aneurysm with dissection throughout the arterial tree.<ref>PMID:15731757</ref> <ref>PMID:16596670</ref> <ref>PMID:16791849</ref> <ref>PMID:19883511</ref> <ref>PMID:22113417</ref> Defects in TGFBR1 are the cause of Loeys-Dietz syndrome type 2A (LDS2A) [MIM:[https://omim.org/entry/608967 608967]]. An aortic aneurysm syndrome with widespread systemic involvement. Physical findings include prominent joint laxity, easy bruising, wide and atrophic scars, velvety and translucent skin with easily visible veins, spontaneous rupture of the spleen or bowel, diffuse arterial aneurysms and dissections, and catastrophic complications of pregnancy, including rupture of the gravid uterus and the arteries, either during pregnancy or in the immediate postpartum period. LDS2 is characterized by the absence of craniofacial abnormalities with the exception of bifid uvula that can be present in some patients. Note=TGFBR1 mutation Gln-487 has been reported to be associated with thoracic aortic aneurysms and dissection (TAAD) (PubMed:16791849). This phenotype, also known as thoracic aortic aneurysms type 5 (AAT5), is distinguised from LDS2A by having aneurysms restricted to thoracic aorta. It is unclear, however, if this condition is fulfilled in individuals bearing Gln-487 mutation, that is why they are considered as LDS2A by the OMIM resource. Defects in TGFBR1 are the cause of multiple self-healing squamous epithelioma (MSSE) [MIM:[https://omim.org/entry/132800 132800]]. A disorder characterized by multiple skin tumors that undergo spontaneous regression. Tumors appear most often on sun-exposed regions, are locally invasive, and undergo spontaneous resolution over a period of months leaving pitted scars.<ref>PMID:21358634</ref>	+	[https://www.uniprot.org/uniprot/TGFR1_HUMAN TGFR1_HUMAN] Defects in TGFBR1 are the cause of Loeys-Dietz syndrome type 1A (LDS1A) [MIM:[https://omim.org/entry/609192 609192]; also known as Furlong syndrome or Loeys-Dietz aortic aneurysm syndrome (LDAS). LDS1 is an aortic aneurysm syndrome with widespread systemic involvement. The disorder is characterized by arterial tortuosity and aneurysms, craniosynostosis, hypertelorism, and bifid uvula or cleft palate. Other findings include exotropy, micrognathia and retrognathia, structural brain abnormalities, intellectual deficit, congenital heart disease, translucent skin, joint hyperlaxity and aneurysm with dissection throughout the arterial tree.<ref>PMID:15731757</ref> <ref>PMID:16596670</ref> <ref>PMID:16791849</ref> <ref>PMID:19883511</ref> <ref>PMID:22113417</ref> Defects in TGFBR1 are the cause of Loeys-Dietz syndrome type 2A (LDS2A) [MIM:[https://omim.org/entry/608967 608967]. An aortic aneurysm syndrome with widespread systemic involvement. Physical findings include prominent joint laxity, easy bruising, wide and atrophic scars, velvety and translucent skin with easily visible veins, spontaneous rupture of the spleen or bowel, diffuse arterial aneurysms and dissections, and catastrophic complications of pregnancy, including rupture of the gravid uterus and the arteries, either during pregnancy or in the immediate postpartum period. LDS2 is characterized by the absence of craniofacial abnormalities with the exception of bifid uvula that can be present in some patients. Note=TGFBR1 mutation Gln-487 has been reported to be associated with thoracic aortic aneurysms and dissection (TAAD) (PubMed:16791849). This phenotype, also known as thoracic aortic aneurysms type 5 (AAT5), is distinguised from LDS2A by having aneurysms restricted to thoracic aorta. It is unclear, however, if this condition is fulfilled in individuals bearing Gln-487 mutation, that is why they are considered as LDS2A by the OMIM resource. Defects in TGFBR1 are the cause of multiple self-healing squamous epithelioma (MSSE) [MIM:[https://omim.org/entry/132800 132800]. A disorder characterized by multiple skin tumors that undergo spontaneous regression. Tumors appear most often on sun-exposed regions, are locally invasive, and undergo spontaneous resolution over a period of months leaving pitted scars.<ref>PMID:21358634</ref>
	== Function ==		== Function ==
-	[[https://www.uniprot.org/uniprot/TGFR1_HUMAN TGFR1_HUMAN]] Transmembrane serine/threonine kinase forming with the TGF-beta type II serine/threonine kinase receptor, TGFBR2, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3. Transduces the TGFB1, TGFB2 and TGFB3 signal from the cell surface to the cytoplasm and is thus regulating a plethora of physiological and pathological processes including cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. The formation of the receptor complex composed of 2 TGFBR1 and 2 TGFBR2 molecules symmetrically bound to the cytokine dimer results in the phosphorylation and the activation of TGFBR1 by the constitutively active TGFBR2. Activated TGFBR1 phosphorylates SMAD2 which dissociates from the receptor and interacts with SMAD4. The SMAD2-SMAD4 complex is subsequently translocated to the nucleus where it modulates the transcription of the TGF-beta-regulated genes. This constitutes the canonical SMAD-dependent TGF-beta signaling cascade. Also involved in non-canonical, SMAD-independent TGF-beta signaling pathways. For instance, TGFBR1 induces TRAF6 autoubiquitination which in turn results in MAP3K7 ubiquitination and activation to trigger apoptosis. Also regulates epithelial to mesenchymal transition through a SMAD-independent signaling pathway through PARD6A phosphorylation and activation.<ref>PMID:7774578</ref> <ref>PMID:8752209</ref> <ref>PMID:8980228</ref> <ref>PMID:9346908</ref> <ref>PMID:15761148</ref> <ref>PMID:16754747</ref> <ref>PMID:18758450</ref>	+	[https://www.uniprot.org/uniprot/TGFR1_HUMAN TGFR1_HUMAN] Transmembrane serine/threonine kinase forming with the TGF-beta type II serine/threonine kinase receptor, TGFBR2, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3. Transduces the TGFB1, TGFB2 and TGFB3 signal from the cell surface to the cytoplasm and is thus regulating a plethora of physiological and pathological processes including cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. The formation of the receptor complex composed of 2 TGFBR1 and 2 TGFBR2 molecules symmetrically bound to the cytokine dimer results in the phosphorylation and the activation of TGFBR1 by the constitutively active TGFBR2. Activated TGFBR1 phosphorylates SMAD2 which dissociates from the receptor and interacts with SMAD4. The SMAD2-SMAD4 complex is subsequently translocated to the nucleus where it modulates the transcription of the TGF-beta-regulated genes. This constitutes the canonical SMAD-dependent TGF-beta signaling cascade. Also involved in non-canonical, SMAD-independent TGF-beta signaling pathways. For instance, TGFBR1 induces TRAF6 autoubiquitination which in turn results in MAP3K7 ubiquitination and activation to trigger apoptosis. Also regulates epithelial to mesenchymal transition through a SMAD-independent signaling pathway through PARD6A phosphorylation and activation.<ref>PMID:7774578</ref> <ref>PMID:8752209</ref> <ref>PMID:8980228</ref> <ref>PMID:9346908</ref> <ref>PMID:15761148</ref> <ref>PMID:16754747</ref> <ref>PMID:18758450</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 24:		Line 22:

	==See Also==		==See Also==
-	*[[TGF-~~ÃÂ²~~ receptor 3D structures\|TGF-~~ÃÂ²~~ receptor 3D structures]]	+	*[[TGF-beta receptor 3D structures\|TGF-beta receptor 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Receptor protein serine/threonine kinase]]~~	+	[[Category: Baum P]]
-	[[Category: Baum, P]]	+	[[Category: Brandl T]]
-	[[Category: Brandl, T]]	+	[[Category: Grauert M]]
-	[[Category: Grauert, M]]	+	[[Category: Heckel A]]
-	[[Category: Heckel, A]]	+	[[Category: Hoerer S]]
-	[[Category: Hoerer, S]]	+	[[Category: Kley JT]]
-	[[Category: Kley~~, J T~~]]	+	[[Category: Mennerich D]]
-	[[Category: Mennerich, D]]	+	[[Category: Park JE]]
-	[[Category: Park~~, J E~~]]	+	[[Category: Roth GJ]]
-	[[Category: Roth~~, G J~~]]	+	[[Category: Schnapp A]]
-	[[Category: Schnapp, A]]	+	[[Category: Schnapp G]]
-	[[Category: Schnapp, G]]	+
-	~~[[Category: Glycoprotein]]~~	+
-	~~[[Category: Kinase]]~~	+
-	~~[[Category: Transferase~~]]	+

OCA at 08:36, 10 November 2021

OCA — Wed, 10 Nov 2021 08:36:41 GMT

←Older revision		Revision as of 08:36, 10 November 2021
Line 3:		Line 3:
	<StructureSection load='2x7o' size='340' side='right'caption='[[2x7o]], [[Resolution\|resolution]] 3.70Å' scene=''>		<StructureSection load='2x7o' size='340' side='right'caption='[[2x7o]], [[Resolution\|resolution]] 3.70Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[2x7o]] is a 5 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=2X7O OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=2X7O FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[2x7o]] is a 5 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=2X7O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2X7O FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ZOP:(3Z)-N-ETHYL-N-METHYL-2-OXO-3-(PHENYL{[4-(PIPERIDIN-1-YLMETHYL)PHENYL]AMINO}METHYLIDENE)-2,3-DIHYDRO-1H-INDOLE-6-CARBOXAMIDE'>ZOP</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZOP:(3Z)-N-ETHYL-N-METHYL-2-OXO-3-(PHENYL{[4-(PIPERIDIN-1-YLMETHYL)PHENYL]AMINO}METHYLIDENE)-2,3-DIHYDRO-1H-INDOLE-6-CARBOXAMIDE'>ZOP</scene></td></tr>
-	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1py5\|1py5]], [[1ias\|1ias]], [[2wou\|2wou]], [[2wot\|2wot]], [[1b6c\|1b6c]], [[1vjy\|1vjy]], [[1rw8\|1rw8]]</td></tr>	+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1py5\|1py5]], [[1ias\|1ias]], [[2wou\|2wou]], [[2wot\|2wot]], [[1b6c\|1b6c]], [[1vjy\|1vjy]], [[1rw8\|1rw8]]</div></td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://en.wikipedia.org/wiki/Receptor_protein_serine/threonine_kinase Receptor protein serine/threonine kinase], with EC number [~~http~~://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.30 2.7.11.30] </span></td></tr>	+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Receptor_protein_serine/threonine_kinase Receptor protein serine/threonine kinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.30 2.7.11.30] </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=2x7o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2x7o OCA], [~~http~~://pdbe.org/2x7o PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=2x7o RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/2x7o PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=2x7o 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=2x7o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2x7o OCA], [https://pdbe.org/2x7o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2x7o RCSB], [https://www.ebi.ac.uk/pdbsum/2x7o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2x7o ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
-	[[~~http~~://www.uniprot.org/uniprot/TGFR1_HUMAN TGFR1_HUMAN]] Defects in TGFBR1 are the cause of Loeys-Dietz syndrome type 1A (LDS1A) [MIM:[~~http~~://omim.org/entry/609192 609192]]; also known as Furlong syndrome or Loeys-Dietz aortic aneurysm syndrome (LDAS). LDS1 is an aortic aneurysm syndrome with widespread systemic involvement. The disorder is characterized by arterial tortuosity and aneurysms, craniosynostosis, hypertelorism, and bifid uvula or cleft palate. Other findings include exotropy, micrognathia and retrognathia, structural brain abnormalities, intellectual deficit, congenital heart disease, translucent skin, joint hyperlaxity and aneurysm with dissection throughout the arterial tree.<ref>PMID:15731757</ref> <ref>PMID:16596670</ref> <ref>PMID:16791849</ref> <ref>PMID:19883511</ref> <ref>PMID:22113417</ref> Defects in TGFBR1 are the cause of Loeys-Dietz syndrome type 2A (LDS2A) [MIM:[~~http~~://omim.org/entry/608967 608967]]. An aortic aneurysm syndrome with widespread systemic involvement. Physical findings include prominent joint laxity, easy bruising, wide and atrophic scars, velvety and translucent skin with easily visible veins, spontaneous rupture of the spleen or bowel, diffuse arterial aneurysms and dissections, and catastrophic complications of pregnancy, including rupture of the gravid uterus and the arteries, either during pregnancy or in the immediate postpartum period. LDS2 is characterized by the absence of craniofacial abnormalities with the exception of bifid uvula that can be present in some patients. Note=TGFBR1 mutation Gln-487 has been reported to be associated with thoracic aortic aneurysms and dissection (TAAD) (PubMed:16791849). This phenotype, also known as thoracic aortic aneurysms type 5 (AAT5), is distinguised from LDS2A by having aneurysms restricted to thoracic aorta. It is unclear, however, if this condition is fulfilled in individuals bearing Gln-487 mutation, that is why they are considered as LDS2A by the OMIM resource. Defects in TGFBR1 are the cause of multiple self-healing squamous epithelioma (MSSE) [MIM:[~~http~~://omim.org/entry/132800 132800]]. A disorder characterized by multiple skin tumors that undergo spontaneous regression. Tumors appear most often on sun-exposed regions, are locally invasive, and undergo spontaneous resolution over a period of months leaving pitted scars.<ref>PMID:21358634</ref>	+	[[https://www.uniprot.org/uniprot/TGFR1_HUMAN TGFR1_HUMAN]] Defects in TGFBR1 are the cause of Loeys-Dietz syndrome type 1A (LDS1A) [MIM:[https://omim.org/entry/609192 609192]]; also known as Furlong syndrome or Loeys-Dietz aortic aneurysm syndrome (LDAS). LDS1 is an aortic aneurysm syndrome with widespread systemic involvement. The disorder is characterized by arterial tortuosity and aneurysms, craniosynostosis, hypertelorism, and bifid uvula or cleft palate. Other findings include exotropy, micrognathia and retrognathia, structural brain abnormalities, intellectual deficit, congenital heart disease, translucent skin, joint hyperlaxity and aneurysm with dissection throughout the arterial tree.<ref>PMID:15731757</ref> <ref>PMID:16596670</ref> <ref>PMID:16791849</ref> <ref>PMID:19883511</ref> <ref>PMID:22113417</ref> Defects in TGFBR1 are the cause of Loeys-Dietz syndrome type 2A (LDS2A) [MIM:[https://omim.org/entry/608967 608967]]. An aortic aneurysm syndrome with widespread systemic involvement. Physical findings include prominent joint laxity, easy bruising, wide and atrophic scars, velvety and translucent skin with easily visible veins, spontaneous rupture of the spleen or bowel, diffuse arterial aneurysms and dissections, and catastrophic complications of pregnancy, including rupture of the gravid uterus and the arteries, either during pregnancy or in the immediate postpartum period. LDS2 is characterized by the absence of craniofacial abnormalities with the exception of bifid uvula that can be present in some patients. Note=TGFBR1 mutation Gln-487 has been reported to be associated with thoracic aortic aneurysms and dissection (TAAD) (PubMed:16791849). This phenotype, also known as thoracic aortic aneurysms type 5 (AAT5), is distinguised from LDS2A by having aneurysms restricted to thoracic aorta. It is unclear, however, if this condition is fulfilled in individuals bearing Gln-487 mutation, that is why they are considered as LDS2A by the OMIM resource. Defects in TGFBR1 are the cause of multiple self-healing squamous epithelioma (MSSE) [MIM:[https://omim.org/entry/132800 132800]]. A disorder characterized by multiple skin tumors that undergo spontaneous regression. Tumors appear most often on sun-exposed regions, are locally invasive, and undergo spontaneous resolution over a period of months leaving pitted scars.<ref>PMID:21358634</ref>
	== Function ==		== Function ==
-	[[~~http~~://www.uniprot.org/uniprot/TGFR1_HUMAN TGFR1_HUMAN]] Transmembrane serine/threonine kinase forming with the TGF-beta type II serine/threonine kinase receptor, TGFBR2, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3. Transduces the TGFB1, TGFB2 and TGFB3 signal from the cell surface to the cytoplasm and is thus regulating a plethora of physiological and pathological processes including cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. The formation of the receptor complex composed of 2 TGFBR1 and 2 TGFBR2 molecules symmetrically bound to the cytokine dimer results in the phosphorylation and the activation of TGFBR1 by the constitutively active TGFBR2. Activated TGFBR1 phosphorylates SMAD2 which dissociates from the receptor and interacts with SMAD4. The SMAD2-SMAD4 complex is subsequently translocated to the nucleus where it modulates the transcription of the TGF-beta-regulated genes. This constitutes the canonical SMAD-dependent TGF-beta signaling cascade. Also involved in non-canonical, SMAD-independent TGF-beta signaling pathways. For instance, TGFBR1 induces TRAF6 autoubiquitination which in turn results in MAP3K7 ubiquitination and activation to trigger apoptosis. Also regulates epithelial to mesenchymal transition through a SMAD-independent signaling pathway through PARD6A phosphorylation and activation.<ref>PMID:7774578</ref> <ref>PMID:8752209</ref> <ref>PMID:8980228</ref> <ref>PMID:9346908</ref> <ref>PMID:15761148</ref> <ref>PMID:16754747</ref> <ref>PMID:18758450</ref>	+	[[https://www.uniprot.org/uniprot/TGFR1_HUMAN TGFR1_HUMAN]] Transmembrane serine/threonine kinase forming with the TGF-beta type II serine/threonine kinase receptor, TGFBR2, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3. Transduces the TGFB1, TGFB2 and TGFB3 signal from the cell surface to the cytoplasm and is thus regulating a plethora of physiological and pathological processes including cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. The formation of the receptor complex composed of 2 TGFBR1 and 2 TGFBR2 molecules symmetrically bound to the cytokine dimer results in the phosphorylation and the activation of TGFBR1 by the constitutively active TGFBR2. Activated TGFBR1 phosphorylates SMAD2 which dissociates from the receptor and interacts with SMAD4. The SMAD2-SMAD4 complex is subsequently translocated to the nucleus where it modulates the transcription of the TGF-beta-regulated genes. This constitutes the canonical SMAD-dependent TGF-beta signaling cascade. Also involved in non-canonical, SMAD-independent TGF-beta signaling pathways. For instance, TGFBR1 induces TRAF6 autoubiquitination which in turn results in MAP3K7 ubiquitination and activation to trigger apoptosis. Also regulates epithelial to mesenchymal transition through a SMAD-independent signaling pathway through PARD6A phosphorylation and activation.<ref>PMID:7774578</ref> <ref>PMID:8752209</ref> <ref>PMID:8980228</ref> <ref>PMID:9346908</ref> <ref>PMID:15761148</ref> <ref>PMID:16754747</ref> <ref>PMID:18758450</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==
-	*[[TGF-~~beta~~ receptor\|TGF-~~beta~~ receptor]]	+	*[[TGF-ÃÂ² receptor 3D structures\|TGF-ÃÂ² receptor 3D structures]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 07:35, 3 April 2019

OCA — Wed, 03 Apr 2019 07:35:10 GMT

←Older revision		Revision as of 07:35, 3 April 2019
Line 1:		Line 1:

	==Crystal structure of TGFbRI complexed with an indolinone inhibitor==		==Crystal structure of TGFbRI complexed with an indolinone inhibitor==
-	<StructureSection load='2x7o' size='340' side='right' caption='[[2x7o]], [[Resolution\|resolution]] 3.70Å' scene=''>	+	<StructureSection load='2x7o' size='340' side='right'caption='[[2x7o]], [[Resolution\|resolution]] 3.70Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[2x7o]] is a 5 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=2X7O OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2X7O FirstGlance]. <br>		<table><tr><td colspan='2'>[[2x7o]] is a 5 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=2X7O OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2X7O FirstGlance]. <br>
Line 30:		Line 30:
	</StructureSection>		</StructureSection>
	[[Category: Human]]		[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Receptor protein serine/threonine kinase]]		[[Category: Receptor protein serine/threonine kinase]]
	[[Category: Baum, P]]		[[Category: Baum, P]]

OCA at 09:45, 3 October 2018

OCA — Wed, 03 Oct 2018 09:45:39 GMT

←Older revision		Revision as of 09:45, 3 October 2018
Line 1:		Line 1:

-	==~~CRYSTAL STRUCTURE OF TGFBRI COMPLEXED WITH AN INDOLINONE INHIBITOR~~==	+	==Crystal structure of TGFbRI complexed with an indolinone inhibitor==
	<StructureSection load='2x7o' size='340' side='right' caption='[[2x7o]], [[Resolution\|resolution]] 3.70Å' scene=''>		<StructureSection load='2x7o' size='340' side='right' caption='[[2x7o]], [[Resolution\|resolution]] 3.70Å' scene=''>
	== Structural highlights ==		== Structural highlights ==

OCA at 23:17, 5 August 2016

OCA — Fri, 05 Aug 2016 23:17:02 GMT

←Older revision		Revision as of 23:17, 5 August 2016
Line 1:		Line 1:
		+
	==CRYSTAL STRUCTURE OF TGFBRI COMPLEXED WITH AN INDOLINONE INHIBITOR==		==CRYSTAL STRUCTURE OF TGFBRI COMPLEXED WITH AN INDOLINONE INHIBITOR==
	<StructureSection load='2x7o' size='340' side='right' caption='[[2x7o]], [[Resolution\|resolution]] 3.70Å' scene=''>		<StructureSection load='2x7o' size='340' side='right' caption='[[2x7o]], [[Resolution\|resolution]] 3.70Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[2x7o]] is a 5 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=2X7O OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2X7O FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[2x7o]] is a 5 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=2X7O OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2X7O FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ZOP:(3Z)-N-ETHYL-N-METHYL-2-OXO-3-(PHENYL{[4-(PIPERIDIN-1-YLMETHYL)PHENYL]AMINO}METHYLIDENE)-2,3-DIHYDRO-1H-INDOLE-6-CARBOXAMIDE'>ZOP</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ZOP:(3Z)-N-ETHYL-N-METHYL-2-OXO-3-(PHENYL{[4-(PIPERIDIN-1-YLMETHYL)PHENYL]AMINO}METHYLIDENE)-2,3-DIHYDRO-1H-INDOLE-6-CARBOXAMIDE'>ZOP</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1py5\|1py5]], [[1ias\|1ias]], [[2wou\|2wou]], [[2wot\|2wot]], [[1b6c\|1b6c]], [[1vjy\|1vjy]], [[1rw8\|1rw8]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1py5\|1py5]], [[1ias\|1ias]], [[2wou\|2wou]], [[2wot\|2wot]], [[1b6c\|1b6c]], [[1vjy\|1vjy]], [[1rw8\|1rw8]]</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein_serine/threonine_kinase Receptor protein serine/threonine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.30 2.7.11.30] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein_serine/threonine_kinase Receptor protein serine/threonine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.30 2.7.11.30] </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=2x7o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2x7o OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2x7o RCSB], [http://www.ebi.ac.uk/pdbsum/2x7o 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=2x7o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2x7o OCA], [http://pdbe.org/2x7o PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2x7o RCSB], [http://www.ebi.ac.uk/pdbsum/2x7o PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2x7o 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 2x7o" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[TGF-beta receptor\|TGF-beta receptor]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Homo sapiens~~]]	+	[[Category: Human]]
	[[Category: Receptor protein serine/threonine kinase]]		[[Category: Receptor protein serine/threonine kinase]]
	[[Category: Baum, P]]		[[Category: Baum, P]]

OCA at 12:44, 18 December 2014

OCA — Thu, 18 Dec 2014 12:44:39 GMT

←Older revision		Revision as of 12:44, 18 December 2014
Line 1:		Line 1:
-	~~{{STRUCTURE_2x7o\| PDB=2x7o \| SCENE= }}~~	+	==CRYSTAL STRUCTURE OF TGFBRI COMPLEXED WITH AN INDOLINONE INHIBITOR==
-	===CRYSTAL STRUCTURE OF TGFBRI COMPLEXED WITH AN INDOLINONE INHIBITOR===	+	<StructureSection load='2x7o' size='340' side='right' caption='[[2x7o]], [[Resolution\|resolution]] 3.70Å' scene=''>
-	{~~{ABSTRACT_PUBMED_20919678}~~}	+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[2x7o]] is a 5 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=2X7O OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2X7O FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ZOP:(3Z)-N-ETHYL-N-METHYL-2-OXO-3-(PHENYL{[4-(PIPERIDIN-1-YLMETHYL)PHENYL]AMINO}METHYLIDENE)-2,3-DIHYDRO-1H-INDOLE-6-CARBOXAMIDE'>ZOP</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1py5\|1py5]], [[1ias\|1ias]], [[2wou\|2wou]], [[2wot\|2wot]], [[1b6c\|1b6c]], [[1vjy\|1vjy]], [[1rw8\|1rw8]]</td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein_serine/threonine_kinase Receptor protein serine/threonine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.30 2.7.11.30] </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=2x7o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2x7o OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2x7o RCSB], [http://www.ebi.ac.uk/pdbsum/2x7o PDBsum]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/TGFR1_HUMAN TGFR1_HUMAN]] Defects in TGFBR1 are the cause of Loeys-Dietz syndrome type 1A (LDS1A) [MIM:[http://omim.org/entry/609192 609192]]; also known as Furlong syndrome or Loeys-Dietz aortic aneurysm syndrome (LDAS). LDS1 is an aortic aneurysm syndrome with widespread systemic involvement. The disorder is characterized by arterial tortuosity and aneurysms, craniosynostosis, hypertelorism, and bifid uvula or cleft palate. Other findings include exotropy, micrognathia and retrognathia, structural brain abnormalities, intellectual deficit, congenital heart disease, translucent skin, joint hyperlaxity and aneurysm with dissection throughout the arterial tree.<ref>PMID:15731757</ref> <ref>PMID:16596670</ref> <ref>PMID:16791849</ref> <ref>PMID:19883511</ref> <ref>PMID:22113417</ref> Defects in TGFBR1 are the cause of Loeys-Dietz syndrome type 2A (LDS2A) [MIM:[http://omim.org/entry/608967 608967]]. An aortic aneurysm syndrome with widespread systemic involvement. Physical findings include prominent joint laxity, easy bruising, wide and atrophic scars, velvety and translucent skin with easily visible veins, spontaneous rupture of the spleen or bowel, diffuse arterial aneurysms and dissections, and catastrophic complications of pregnancy, including rupture of the gravid uterus and the arteries, either during pregnancy or in the immediate postpartum period. LDS2 is characterized by the absence of craniofacial abnormalities with the exception of bifid uvula that can be present in some patients. Note=TGFBR1 mutation Gln-487 has been reported to be associated with thoracic aortic aneurysms and dissection (TAAD) (PubMed:16791849). This phenotype, also known as thoracic aortic aneurysms type 5 (AAT5), is distinguised from LDS2A by having aneurysms restricted to thoracic aorta. It is unclear, however, if this condition is fulfilled in individuals bearing Gln-487 mutation, that is why they are considered as LDS2A by the OMIM resource. Defects in TGFBR1 are the cause of multiple self-healing squamous epithelioma (MSSE) [MIM:[http://omim.org/entry/132800 132800]]. A disorder characterized by multiple skin tumors that undergo spontaneous regression. Tumors appear most often on sun-exposed regions, are locally invasive, and undergo spontaneous resolution over a period of months leaving pitted scars.<ref>PMID:21358634</ref>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/TGFR1_HUMAN TGFR1_HUMAN]] Transmembrane serine/threonine kinase forming with the TGF-beta type II serine/threonine kinase receptor, TGFBR2, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3. Transduces the TGFB1, TGFB2 and TGFB3 signal from the cell surface to the cytoplasm and is thus regulating a plethora of physiological and pathological processes including cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. The formation of the receptor complex composed of 2 TGFBR1 and 2 TGFBR2 molecules symmetrically bound to the cytokine dimer results in the phosphorylation and the activation of TGFBR1 by the constitutively active TGFBR2. Activated TGFBR1 phosphorylates SMAD2 which dissociates from the receptor and interacts with SMAD4. The SMAD2-SMAD4 complex is subsequently translocated to the nucleus where it modulates the transcription of the TGF-beta-regulated genes. This constitutes the canonical SMAD-dependent TGF-beta signaling cascade. Also involved in non-canonical, SMAD-independent TGF-beta signaling pathways. For instance, TGFBR1 induces TRAF6 autoubiquitination which in turn results in MAP3K7 ubiquitination and activation to trigger apoptosis. Also regulates epithelial to mesenchymal transition through a SMAD-independent signaling pathway through PARD6A phosphorylation and activation.<ref>PMID:7774578</ref> <ref>PMID:8752209</ref> <ref>PMID:8980228</ref> <ref>PMID:9346908</ref> <ref>PMID:15761148</ref> <ref>PMID:16754747</ref> <ref>PMID:18758450</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Inhibition of transforming growth factor beta (TGFbeta) type I receptor (Alk5) offers a novel approach for the treatment of fibrotic diseases and cancer. Indolinones substituted in position 6 were identified as a new chemotype inhibiting TGFbetaRI concomitant with a low cross-reactivity among the human kinome. A subset of compounds showed additional inhibition of platelet-derived growth factor receptor alpha (PDGFRalpha), contributing to an interesting pharmacological profile. In contrast, p38 kinase, which is often inhibited by TGFbetaRI inhibitors, was not targeted by derivatives based on the indolinone chemotype. Guided by an X-ray structure of lead compound 5 (BIBF0775) soaked into the kinase domain of TGFbetaRI, optimization furnished potent and selective inhibitors of TGFbetaRI. Potent inhibition translated well into good inhibition of TGFbetaRI-mediated phosphorylation of Smad2/3, demonstrating efficacy in a cellular setting. Optimized compounds were extensively profiled on a 232-kinase panel and showed low cross-reactivities within the human kinome.

-	~~==Disease==~~	+	Design, Synthesis, and Evaluation of Indolinones as Inhibitors of the Transforming Growth Factor beta Receptor I (TGFbetaRI).,Roth GJ, Heckel A, Brandl T, Grauert M, Hoerer S, Kley JT, Schnapp G, Baum P, Mennerich D, Schnapp A, Park JE J Med Chem. 2010 Oct 4. PMID:20919678<ref>PMID:20919678</ref>
-	[[http://www.uniprot.org/uniprot/TGFR1_HUMAN TGFR1_HUMAN]] Defects in TGFBR1 are the cause of Loeys-Dietz syndrome type 1A (LDS1A) [MIM:[http://omim.org/entry/609192 609192]]; also known as Furlong syndrome or Loeys-Dietz aortic aneurysm syndrome (LDAS). LDS1 is an aortic aneurysm syndrome with widespread systemic involvement. The disorder is characterized by arterial tortuosity and aneurysms, ~~craniosynostosis, hypertelorism~~, and bifid uvula or cleft palate. Other findings include exotropy, micrognathia and retrognathia, structural brain abnormalities, intellectual deficit, congenital heart disease, translucent skin, joint hyperlaxity and aneurysm with dissection throughout the ~~arterial tree.<ref>PMID:15731757</ref><ref>PMID:16596670</ref><ref>PMID:16791849</ref><ref>PMID:19883511</ref><ref>PMID:22113417</ref> Defects in TGFBR1 are the cause of Loeys-Dietz syndrome type 2A~~ (~~LDS2A~~) ~~[MIM:[http://omim.org/entry/608967 608967]]. An aortic aneurysm syndrome with widespread systemic involvement~~. ~~Physical findings include prominent joint laxity~~, ~~easy bruising~~, ~~wide and atrophic scars~~, ~~velvety and translucent skin with easily visible veins~~, ~~spontaneous rupture of the spleen or bowel~~, ~~diffuse arterial aneurysms and dissections~~, ~~and catastrophic complications of pregnancy~~, ~~including rupture of the gravid uterus and the arteries~~, either during pregnancy or in the immediate postpartum period. LDS2 is characterized by the absence of craniofacial abnormalities with the exception of bifid uvula that can be present in some patients. Note=TGFBR1 mutation Gln-487 has been reported to be associated with thoracic aortic aneurysms and dissection (TAAD) (PubMed:16791849). This phenotype, ~~also known as thoracic aortic aneurysms type 5 (AAT5)~~, ~~is distinguised from LDS2A by having aneurysms restricted to thoracic aorta. It is unclear~~, ~~however, if this condition is fulfilled in individuals bearing Gln-487 mutation, that is why they are considered as LDS2A by the OMIM resource~~. ~~Defects in TGFBR1 are the cause of multiple self-healing squamous epithelioma (MSSE) [MIM~~:[http://omim.org/entry/132800 132800]]. A disorder characterized by multiple skin tumors that undergo spontaneous regression. Tumors appear most often on sun-exposed regions, are locally invasive, and undergo spontaneous resolution over a period of months leaving pitted scars.<ref>PMID:~~21358634~~</ref>	+

-	~~==Function==~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[http:~~/~~/www.uniprot.org/uniprot/TGFR1_HUMAN TGFR1_HUMAN]] Transmembrane serine/threonine kinase forming with the TGF-beta type II serine/threonine kinase receptor~~, ~~TGFBR2, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3. Transduces the TGFB1, TGFB2 and TGFB3 signal from the cell surface to the cytoplasm and is thus regulating~~ a plethora of physiological and pathological processes including cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. The formation of the ~~receptor complex composed of 2 TGFBR1 and 2 TGFBR2 molecules symmetrically bound to the cytokine dimer results in the phosphorylation and the activation of TGFBR1 by the constitutively active TGFBR2~~. ~~Activated TGFBR1 phosphorylates SMAD2 which dissociates from the receptor and interacts with SMAD4~~. ~~The SMAD2-SMAD4 complex is subsequently translocated to the nucleus where it modulates the transcription~~ of the TGF-beta-regulated genes. This constitutes the canonical SMAD-dependent TGF-beta signaling cascade. Also involved in non-canonical, SMAD-independent TGF-beta signaling pathways. For instance, TGFBR1 induces TRAF6 autoubiquitination which in turn results in MAP3K7 ubiquitination and activation to trigger apoptosis. Also regulates epithelial to mesenchymal transition through a SMAD-independent signaling pathway through PARD6A phosphorylation and activation.<~~ref~~>~~PMID:7774578~~</~~ref~~>~~<ref>PMID:8752209</ref><ref>PMID:8980228</ref><ref>PMID:9346908</ref><ref>PMID:15761148</ref><ref>PMID:16754747</ref><ref>PMID:18758450</ref>~~	+	</div>
-		+	== References ==
-	==~~About this Structure==~~	+	<references/>
-	[[2x7o]] is a 5 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=2X7O OCA].	+	__TOC__
-		+	</StructureSection>
-	~~==Reference~~==	+
-	~~<ref group="xtra">PMID:020919678</ref>~~<references ~~group="xtra"~~/><~~references~~/>	+
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Receptor protein serine/threonine kinase]]		[[Category: Receptor protein serine/threonine kinase]]
-	[[Category: Baum, P.]]	+	[[Category: Baum, P]]
-	[[Category: Brandl, T.]]	+	[[Category: Brandl, T]]
-	[[Category: Grauert, M.]]	+	[[Category: Grauert, M]]
-	[[Category: Heckel, A.]]	+	[[Category: Heckel, A]]
-	[[Category: Hoerer, S.]]	+	[[Category: Hoerer, S]]
-	[[Category: Kley, J T.]]	+	[[Category: Kley, J T]]
-	[[Category: Mennerich, D.]]	+	[[Category: Mennerich, D]]
-	[[Category: Park, J E.]]	+	[[Category: Park, J E]]
-	[[Category: Roth, G J.]]	+	[[Category: Roth, G J]]
-	[[Category: Schnapp, A.]]	+	[[Category: Schnapp, A]]
-	[[Category: Schnapp, G.]]	+	[[Category: Schnapp, G]]
	[[Category: Glycoprotein]]		[[Category: Glycoprotein]]
	[[Category: Kinase]]		[[Category: Kinase]]
	[[Category: Transferase]]		[[Category: Transferase]]

OCA at 07:12, 25 March 2013

OCA — Mon, 25 Mar 2013 07:12:52 GMT

←Older revision		Revision as of 07:12, 25 March 2013
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-	[[Image:2x7o.png\|left\|200px]]
-
-	<!--
-	The line below this paragraph, containing "STRUCTURE_2x7o", 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_2x7o\| PDB=2x7o \| SCENE= }}		{{STRUCTURE_2x7o\| PDB=2x7o \| SCENE= }}
-
	===CRYSTAL STRUCTURE OF TGFBRI COMPLEXED WITH AN INDOLINONE INHIBITOR===		===CRYSTAL STRUCTURE OF TGFBRI COMPLEXED WITH AN INDOLINONE INHIBITOR===
		+	{{ABSTRACT_PUBMED_20919678}}

		+	==Disease==
		+	[[http://www.uniprot.org/uniprot/TGFR1_HUMAN TGFR1_HUMAN]] Defects in TGFBR1 are the cause of Loeys-Dietz syndrome type 1A (LDS1A) [MIM:[http://omim.org/entry/609192 609192]]; also known as Furlong syndrome or Loeys-Dietz aortic aneurysm syndrome (LDAS). LDS1 is an aortic aneurysm syndrome with widespread systemic involvement. The disorder is characterized by arterial tortuosity and aneurysms, craniosynostosis, hypertelorism, and bifid uvula or cleft palate. Other findings include exotropy, micrognathia and retrognathia, structural brain abnormalities, intellectual deficit, congenital heart disease, translucent skin, joint hyperlaxity and aneurysm with dissection throughout the arterial tree.<ref>PMID:15731757</ref><ref>PMID:16596670</ref><ref>PMID:16791849</ref><ref>PMID:19883511</ref><ref>PMID:22113417</ref> Defects in TGFBR1 are the cause of Loeys-Dietz syndrome type 2A (LDS2A) [MIM:[http://omim.org/entry/608967 608967]]. An aortic aneurysm syndrome with widespread systemic involvement. Physical findings include prominent joint laxity, easy bruising, wide and atrophic scars, velvety and translucent skin with easily visible veins, spontaneous rupture of the spleen or bowel, diffuse arterial aneurysms and dissections, and catastrophic complications of pregnancy, including rupture of the gravid uterus and the arteries, either during pregnancy or in the immediate postpartum period. LDS2 is characterized by the absence of craniofacial abnormalities with the exception of bifid uvula that can be present in some patients. Note=TGFBR1 mutation Gln-487 has been reported to be associated with thoracic aortic aneurysms and dissection (TAAD) (PubMed:16791849). This phenotype, also known as thoracic aortic aneurysms type 5 (AAT5), is distinguised from LDS2A by having aneurysms restricted to thoracic aorta. It is unclear, however, if this condition is fulfilled in individuals bearing Gln-487 mutation, that is why they are considered as LDS2A by the OMIM resource. Defects in TGFBR1 are the cause of multiple self-healing squamous epithelioma (MSSE) [MIM:[http://omim.org/entry/132800 132800]]. A disorder characterized by multiple skin tumors that undergo spontaneous regression. Tumors appear most often on sun-exposed regions, are locally invasive, and undergo spontaneous resolution over a period of months leaving pitted scars.<ref>PMID:21358634</ref>

-	~~<!--~~	+	==Function==
-	~~The line below this paragraph, {{ABSTRACT_PUBMED_20919678}}, adds the Publication Abstract to the page~~	+	[[http://www.uniprot.org/uniprot/TGFR1_HUMAN TGFR1_HUMAN]] Transmembrane serine/threonine kinase forming with the TGF-beta type II serine/threonine kinase receptor, TGFBR2, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3. Transduces the TGFB1, TGFB2 and TGFB3 signal from the cell surface to the cytoplasm and is thus regulating a plethora of physiological and pathological processes including cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. The formation of the receptor complex composed of 2 TGFBR1 and 2 TGFBR2 molecules symmetrically bound to the cytokine dimer results in the phosphorylation and the activation of TGFBR1 by the constitutively active TGFBR2. Activated TGFBR1 phosphorylates SMAD2 which dissociates from the receptor and interacts with SMAD4. The SMAD2-SMAD4 complex is subsequently translocated to the nucleus where it modulates the transcription of the TGF-beta-regulated genes. This constitutes the canonical SMAD-dependent TGF-beta signaling cascade. Also involved in non-canonical, SMAD-independent TGF-beta signaling pathways. For instance, TGFBR1 induces TRAF6 autoubiquitination which in turn results in MAP3K7 ubiquitination and activation to trigger apoptosis. Also regulates epithelial to mesenchymal transition through a SMAD-independent signaling pathway through PARD6A phosphorylation and activation.<ref>PMID:7774578</ref><ref>PMID:8752209</ref><ref>PMID:8980228</ref><ref>PMID:9346908</ref><ref>PMID:15761148</ref><ref>PMID:16754747</ref><ref>PMID:18758450</ref>
-	~~(as it appears on PubMed at~~ http://www.~~pubmed~~.~~gov)~~, ~~where 20919678~~ is the ~~PubMed ID number~~.	+
-	-->	+
-	~~{{ABSTRACT_PUBMED_20919678}}~~	+

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

	==Reference==		==Reference==
-	<ref group="xtra">PMID:020919678</ref><references group="xtra"/>	+	<ref group="xtra">PMID:020919678</ref><references group="xtra"/><references/>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Receptor protein serine/threonine kinase]]		[[Category: Receptor protein serine/threonine kinase]]
Line 36:		Line 27:
	[[Category: Schnapp, A.]]		[[Category: Schnapp, A.]]
	[[Category: Schnapp, G.]]		[[Category: Schnapp, G.]]
		+	[[Category: Glycoprotein]]
		+	[[Category: Kinase]]
		+	[[Category: Transferase]]

OCA: Protected "2x7o" [edit=sysop:move=sysop]

OCA — Wed, 25 May 2011 05:55:52 GMT

Protected "2x7o" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:55, 25 May 2011

OCA at 05:55, 25 May 2011

OCA — Wed, 25 May 2011 05:55:46 GMT

←Older revision		Revision as of 05:55, 25 May 2011
Line 1:		Line 1:
-	~~{{Seed}}~~	+	[[Image:2x7o.png\|left\|200px]]
-	[[Image:2x7o.~~jpg~~\|left\|200px]]	+

	<!--		<!--
Line 20:		Line 19:

	==About this Structure==		==About this Structure==
-	~~2X7O~~ is a 5 ~~chains~~ structure with ~~sequences~~ 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=2X7O OCA].	+	[[2x7o]] is a 5 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=2X7O OCA].

	==Reference==		==Reference==
-	<ref group="xtra">PMID:~~20919678~~</ref><references group="xtra"/>	+	<ref group="xtra">PMID:020919678</ref><references group="xtra"/>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Receptor protein serine/threonine kinase]]		[[Category: Receptor protein serine/threonine kinase]]
Line 37:		Line 36:
	[[Category: Schnapp, A.]]		[[Category: Schnapp, A.]]
	[[Category: Schnapp, G.]]		[[Category: Schnapp, G.]]
-	[[Category: Glycoprotein]]
-	[[Category: Kinase]]
-	[[Category: Transferase]]
-
-	''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Oct 20 06:35:12 2010''