5qim - Revision history

OCA at 13:45, 6 March 2024

2024-03-06T13:45:02Z

←Older revision		Revision as of 13:45, 6 March 2024
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	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[5qim]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5QIM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5QIM FirstGlance]. <br>		<table><tr><td colspan='2'>[[5qim]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5QIM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5QIM FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=J2Y:N-{4-[3-(5-methoxypyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}acetamide'>J2Y</scene></td></tr>	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 1.75Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=J2Y:N-{4-[3-(5-methoxypyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}acetamide'>J2Y</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=5qim FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5qim OCA], [https://pdbe.org/5qim PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5qim RCSB], [https://www.ebi.ac.uk/pdbsum/5qim PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5qim 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=5qim FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5qim OCA], [https://pdbe.org/5qim PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5qim RCSB], [https://www.ebi.ac.uk/pdbsum/5qim PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5qim ProSAT]</span></td></tr>
	</table>		</table>
Line 11:		Line 12:
	== 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;">
-	== Publication Abstract from PubMed ==
-	The multifunctional cytokine TGFbeta plays a central role in regulating antitumor immunity. It has been postulated that inhibition of TGFbeta signaling in concert with checkpoint blockade will provide improved and durable immune response against tumors. Herein, we describe a novel series of 4-azaindole TGFbeta receptor kinase inhibitors with excellent selectivity for TGFbeta receptor 1 kinase. The combination of compound 3f and an antimouse-PD-1 antibody demonstrated significantly improved antitumor efficacy compared to either treatment alone in a murine tumor model.
-
-	Discovery of 4-Azaindole Inhibitors of TGFbetaRI as Immuno-oncology Agents.,Zhang Y, Zhao Y, Tebben AJ, Sheriff S, Ruzanov M, Fereshteh MP, Fan Y, Lippy J, Swanson J, Ho CP, Wautlet BS, Rose A, Parrish K, Yang Z, Donnell AF, Zhang L, Fink BE, Vite GD, Augustine-Rauch K, Fargnoli J, Borzilleri RM ACS Med Chem Lett. 2018 Oct 17;9(11):1117-1122. doi:, 10.1021/acsmedchemlett.8b00357. eCollection 2018 Nov 8. PMID:30429955<ref>PMID:30429955</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 5qim" style="background-color:#fffaf0;"></div>

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

OCA at 03:49, 2 October 2022

2022-10-02T03:49:13Z

←Older revision		Revision as of 03:49, 2 October 2022
Line 3:		Line 3:
	<StructureSection load='5qim' size='340' side='right'caption='[[5qim]], [[Resolution\|resolution]] 1.75Å' scene=''>		<StructureSection load='5qim' size='340' side='right'caption='[[5qim]], [[Resolution\|resolution]] 1.75Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5qim]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5QIM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5QIM FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5qim]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5QIM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5QIM FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=J2Y:N-{4-[3-(5-methoxypyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}acetamide'>J2Y</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=J2Y:N-{4-[3-(5-methoxypyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}acetamide'>J2Y</scene></td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">TGFBR1, ALK5, SKR4 ([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/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=5qim FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5qim OCA], [https://pdbe.org/5qim PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5qim RCSB], [https://www.ebi.ac.uk/pdbsum/5qim PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5qim 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=5qim FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5qim OCA], [https://pdbe.org/5qim PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5qim RCSB], [https://www.ebi.ac.uk/pdbsum/5qim PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5qim 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: Sheriff S]]
-	[[Category: Sheriff, S]]	+
-	~~[[Category: Alk5]]~~	+
-	~~[[Category: Kinase domain]]~~	+
-	~~[[Category: Sb431542]]~~	+
-	~~[[Category: Transferase]]~~	+
-	~~[[Category: Transferase-transferase inhibitor complex~~]]	+

OCA at 09:27, 12 May 2021

2021-05-12T09:27:14Z

←Older revision		Revision as of 09:27, 12 May 2021
Line 1:		Line 1:

	==TGF-BETA RECEPTOR TYPE 1 KINASE DOMAIN (T204D) IN COMPLEX WITH N-{4-[3-(5-METHOXYPYRIDIN-2-YL)-1H-PYRROLO[3,2-B] PYRIDIN-2-YL]PYRIDIN-2-YL}ACETAMIDE==		==TGF-BETA RECEPTOR TYPE 1 KINASE DOMAIN (T204D) IN COMPLEX WITH N-{4-[3-(5-METHOXYPYRIDIN-2-YL)-1H-PYRROLO[3,2-B] PYRIDIN-2-YL]PYRIDIN-2-YL}ACETAMIDE==
-	<StructureSection load='5qim' size='340' side='right' caption='[[5qim]], [[Resolution\|resolution]] 1.75Å' scene=''>	+	<StructureSection load='5qim' size='340' side='right'caption='[[5qim]], [[Resolution\|resolution]] 1.75Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5qim]] is a 1 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5QIM OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5QIM FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5qim]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5QIM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5QIM FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=J2Y:N-{4-[3-(5-methoxypyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}acetamide'>J2Y</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=J2Y:N-{4-[3-(5-methoxypyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}acetamide'>J2Y</scene></td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">TGFBR1, ALK5, SKR4 ([~~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">TGFBR1, ALK5, SKR4 ([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/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=5qim FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5qim OCA], [~~http~~://pdbe.org/5qim PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5qim RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5qim PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5qim 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=5qim FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5qim OCA], [https://pdbe.org/5qim PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5qim RCSB], [https://www.ebi.ac.uk/pdbsum/5qim PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5qim 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 22:		Line 22:
	</div>		</div>
	<div class="pdbe-citations 5qim" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 5qim" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[TGF-ÃÂ² receptor 3D structures\|TGF-ÃÂ² receptor 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
Line 27:		Line 30:
	</StructureSection>		</StructureSection>
	[[Category: Human]]		[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Receptor protein serine/threonine kinase]]		[[Category: Receptor protein serine/threonine kinase]]
	[[Category: Sheriff, S]]		[[Category: Sheriff, S]]

OCA at 08:29, 26 December 2018

2018-12-26T08:29:29Z

←Older revision		Revision as of 08:29, 26 December 2018
Line 3:		Line 3:
	<StructureSection load='5qim' size='340' side='right' caption='[[5qim]], [[Resolution\|resolution]] 1.75Å' scene=''>		<StructureSection load='5qim' size='340' side='right' caption='[[5qim]], [[Resolution\|resolution]] 1.75Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5qim]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5QIM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5QIM FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5qim]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5QIM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5QIM FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=J2Y:N-{4-[3-(5-methoxypyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}acetamide'>J2Y</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=J2Y:N-{4-[3-(5-methoxypyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}acetamide'>J2Y</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">TGFBR1, ALK5, SKR4 ([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/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=5qim FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5qim OCA], [http://pdbe.org/5qim PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5qim RCSB], [http://www.ebi.ac.uk/pdbsum/5qim PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5qim ProSAT]</span></td></tr>		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5qim FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5qim OCA], [http://pdbe.org/5qim PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5qim RCSB], [http://www.ebi.ac.uk/pdbsum/5qim PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5qim ProSAT]</span></td></tr>
Line 12:		Line 13:
	== 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>		[[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 ==
		+	The multifunctional cytokine TGFbeta plays a central role in regulating antitumor immunity. It has been postulated that inhibition of TGFbeta signaling in concert with checkpoint blockade will provide improved and durable immune response against tumors. Herein, we describe a novel series of 4-azaindole TGFbeta receptor kinase inhibitors with excellent selectivity for TGFbeta receptor 1 kinase. The combination of compound 3f and an antimouse-PD-1 antibody demonstrated significantly improved antitumor efficacy compared to either treatment alone in a murine tumor model.
		+
		+	Discovery of 4-Azaindole Inhibitors of TGFbetaRI as Immuno-oncology Agents.,Zhang Y, Zhao Y, Tebben AJ, Sheriff S, Ruzanov M, Fereshteh MP, Fan Y, Lippy J, Swanson J, Ho CP, Wautlet BS, Rose A, Parrish K, Yang Z, Donnell AF, Zhang L, Fink BE, Vite GD, Augustine-Rauch K, Fargnoli J, Borzilleri RM ACS Med Chem Lett. 2018 Oct 17;9(11):1117-1122. doi:, 10.1021/acsmedchemlett.8b00357. eCollection 2018 Nov 8. PMID:30429955<ref>PMID:30429955</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 5qim" style="background-color:#fffaf0;"></div>
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Receptor protein serine/threonine kinase]]		[[Category: Receptor protein serine/threonine kinase]]
	[[Category: Sheriff, S]]		[[Category: Sheriff, S]]

OCA at 06:43, 31 October 2018

2018-10-31T06:43:44Z

←Older revision		Revision as of 06:43, 31 October 2018
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry 5qim is ON HOLD until Paper Publication~~	+	==TGF-BETA RECEPTOR TYPE 1 KINASE DOMAIN (T204D) IN COMPLEX WITH N-{4-[3-(5-METHOXYPYRIDIN-2-YL)-1H-PYRROLO[3,2-B] PYRIDIN-2-YL]PYRIDIN-2-YL}ACETAMIDE==
-		+	<StructureSection load='5qim' size='340' side='right' caption='[[5qim]], [[Resolution\|resolution]] 1.75Å' scene=''>
-	~~Authors: Sheriff, S.~~	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>[[5qim]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5QIM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5QIM FirstGlance]. <br>
-	~~Description:~~ TGF-BETA RECEPTOR TYPE 1 KINASE DOMAIN (T204D) IN COMPLEX WITH N-{4-[3-(5-METHOXYPYRIDIN-2-YL)-1H-PYRROLO[3,2-B] PYRIDIN-2-YL]PYRIDIN-2-YL}ACETAMIDE	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=J2Y:N-{4-[3-(5-methoxypyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}acetamide'>J2Y</scene></td></tr>
-	[[Category: ~~Unreleased Structures~~]]	+	<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=5qim FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5qim OCA], [http://pdbe.org/5qim PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5qim RCSB], [http://www.ebi.ac.uk/pdbsum/5qim PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5qim ProSAT]</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>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Receptor protein serine/threonine kinase]]
	[[Category: Sheriff, S]]		[[Category: Sheriff, S]]
		+	[[Category: Alk5]]
		+	[[Category: Kinase domain]]
		+	[[Category: Sb431542]]
		+	[[Category: Transferase]]
		+	[[Category: Transferase-transferase inhibitor complex]]

OCA at 05:51, 12 September 2018

2018-09-12T05:51:52Z

←Older revision		Revision as of 05:51, 12 September 2018
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 5qim is ON HOLD	+	The entry 5qim is ON HOLD until Paper Publication

	Authors: Sheriff, S.		Authors: Sheriff, S.

OCA: Protected "5qim" [edit=sysop:move=sysop]

2018-08-15T14:34:40Z

Protected "5qim" [edit=sysop:move=sysop]

←Older revision

Revision as of 14:34, 15 August 2018

OCA: New page: '''Unreleased structure''' The entry 5qim is ON HOLD Authors: Sheriff, S. Description: TGF-BETA RECEPTOR TYPE 1 KINASE DOMAIN (T204D) IN COMPLEX WITH N-{4-[3-(5-METHOXYPYRIDIN-2-YL)-1H...

2018-08-15T14:34:39Z

New page: '''Unreleased structure''' The entry 5qim is ON HOLD Authors: Sheriff, S. Description: TGF-BETA RECEPTOR TYPE 1 KINASE DOMAIN (T204D) IN COMPLEX WITH N-{4-[3-(5-METHOXYPYRIDIN-2-YL)-1H...

New page

'''Unreleased structure'''

The entry 5qim is ON HOLD

Authors: Sheriff, S.

Description: TGF-BETA RECEPTOR TYPE 1 KINASE DOMAIN (T204D) IN COMPLEX WITH N-{4-[3-(5-METHOXYPYRIDIN-2-YL)-1H-PYRROLO[3,2-B] PYRIDIN-2-YL]PYRIDIN-2-YL}ACETAMIDE
[[Category: Unreleased Structures]]
[[Category: Sheriff, S]]