5wr7 - Revision history

OCA at 08:44, 19 December 2018

OCA — Wed, 19 Dec 2018 08:44:17 GMT

←Older revision		Revision as of 08:44, 19 December 2018
Line 3:		Line 3:
	<StructureSection load='5wr7' size='340' side='right' caption='[[5wr7]], [[Resolution\|resolution]] 2.76Å' scene=''>		<StructureSection load='5wr7' size='340' side='right' caption='[[5wr7]], [[Resolution\|resolution]] 2.76Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5wr7]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WR7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5WR7 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5wr7]] 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=5WR7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5WR7 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=RCH:N-tert-butyl-2-[2-[6,6-dimethyl-8-(methylsulfonylamino)-11-oxidanylidene-naphtho[2,3-b][1]benzofuran-3-yl]ethynyl]-6-methyl-pyridine-4-carboxamide'>RCH</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=RCH:N-tert-butyl-2-[2-[6,6-dimethyl-8-(methylsulfonylamino)-11-oxidanylidene-naphtho[2,3-b][1]benzofuran-3-yl]ethynyl]-6-methyl-pyridine-4-carboxamide'>RCH</scene></td></tr>
	<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></td></tr>		<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">NTRK1, MTC, TRK, TRKA ([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-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </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-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </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=5wr7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wr7 OCA], [http://pdbe.org/5wr7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5wr7 RCSB], [http://www.ebi.ac.uk/pdbsum/5wr7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5wr7 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=5wr7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wr7 OCA], [http://pdbe.org/5wr7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5wr7 RCSB], [http://www.ebi.ac.uk/pdbsum/5wr7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5wr7 ProSAT]</span></td></tr>
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	== Function ==		== Function ==
	[[http://www.uniprot.org/uniprot/NTRK1_HUMAN NTRK1_HUMAN]] Receptor tyrosine kinase involved in the development and the maturation of the central and peripheral nervous systems through regulation of proliferation, differentiation and survival of sympathetic and nervous neurons. High affinity receptor for NGF which is its primary ligand, it can also bind and be activated by NTF3/neurotrophin-3. However, NTF3 only supports axonal extension through NTRK1 but has no effect on neuron survival. Upon dimeric NGF ligand-binding, undergoes homodimerization, autophosphorylation and activation. Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades driving cell survival and differentiation. Through SHC1 and FRS2 activates a GRB2-Ras-MAPK cascade that regulates cell differentiation and survival. Through PLCG1 controls NF-Kappa-B activation and the transcription of genes involved in cell survival. Through SHC1 and SH2B1 controls a Ras-PI3 kinase-AKT1 signaling cascade that is also regulating survival. In absence of ligand and activation, may promote cell death, making the survival of neurons dependent on trophic factors.<ref>PMID:1850821</ref> <ref>PMID:1849459</ref> <ref>PMID:8325889</ref> <ref>PMID:8155326</ref> <ref>PMID:11244088</ref> <ref>PMID:15488758</ref> Isoform TrkA-III is resistant to NGF, constitutively activates AKT1 and NF-kappa-B and is unable to activate the Ras-MAPK signaling cascade. Antagonizes the anti-proliferative NGF-NTRK1 signaling that promotes neuronal precursors differentiation. Isoform TrkA-III promotes angiogenesis and has oncogenic activity when overexpressed.<ref>PMID:1850821</ref> <ref>PMID:1849459</ref> <ref>PMID:8325889</ref> <ref>PMID:8155326</ref> <ref>PMID:11244088</ref> <ref>PMID:15488758</ref>		[[http://www.uniprot.org/uniprot/NTRK1_HUMAN NTRK1_HUMAN]] Receptor tyrosine kinase involved in the development and the maturation of the central and peripheral nervous systems through regulation of proliferation, differentiation and survival of sympathetic and nervous neurons. High affinity receptor for NGF which is its primary ligand, it can also bind and be activated by NTF3/neurotrophin-3. However, NTF3 only supports axonal extension through NTRK1 but has no effect on neuron survival. Upon dimeric NGF ligand-binding, undergoes homodimerization, autophosphorylation and activation. Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades driving cell survival and differentiation. Through SHC1 and FRS2 activates a GRB2-Ras-MAPK cascade that regulates cell differentiation and survival. Through PLCG1 controls NF-Kappa-B activation and the transcription of genes involved in cell survival. Through SHC1 and SH2B1 controls a Ras-PI3 kinase-AKT1 signaling cascade that is also regulating survival. In absence of ligand and activation, may promote cell death, making the survival of neurons dependent on trophic factors.<ref>PMID:1850821</ref> <ref>PMID:1849459</ref> <ref>PMID:8325889</ref> <ref>PMID:8155326</ref> <ref>PMID:11244088</ref> <ref>PMID:15488758</ref> Isoform TrkA-III is resistant to NGF, constitutively activates AKT1 and NF-kappa-B and is unable to activate the Ras-MAPK signaling cascade. Antagonizes the anti-proliferative NGF-NTRK1 signaling that promotes neuronal precursors differentiation. Isoform TrkA-III promotes angiogenesis and has oncogenic activity when overexpressed.<ref>PMID:1850821</ref> <ref>PMID:1849459</ref> <ref>PMID:8325889</ref> <ref>PMID:8155326</ref> <ref>PMID:11244088</ref> <ref>PMID:15488758</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Members of the tropomyosin receptor kinase (TRK) family are expressed in their constitutively activated forms as a result of a gene fusion that occurs across a wide variety of cancer types. We have identified CH7057288 as a potent and selective TRK inhibitor that belongs to a novel chemical class. CH7057288 showed selective inhibitory activity against TRKA, TRKB, and TRKC in cell-free kinase assays and suppressed proliferation of TRK fusion-positive cell lines, but not that of TRK-negative cell lines. Strong in vivo tumor growth inhibition was observed in subcutaneously implanted xenograft tumor models of TRK fusion-positive cells. Furthermore, in an intracranial implantation model mimicking brain metastasis, CH7057288 significantly induced tumor regression and improved event-free survival. Recently, resistant mutations in the kinase domain of TRK have been reported in patients who show disease progression after treatment with the TRK inhibitors now under clinical development. Our compound maintained similar levels of in vitro and in vivo activity against one of these resistant mutants as it did to wild-type TRK. An X-ray crystal structure of the TRKA and CH7057288 complex supported the activity against the mutant. In addition, gene expression analysis revealed that CH7057288 suppressed MAPK and E2F pathways as downstream signaling of TRK fusion. Therefore, CH7057288 could be a promising therapeutic agent for TRK fusion-positive cancer.
		+
		+	Selective TRK Inhibitor CH7057288 against TRK Fusion-Driven Cancer.,Tanaka H, Sase H, Tsukaguchi T, Hasegawa M, Tanimura H, Yoshida M, Sakata K, Fujii T, Tachibana Y, Takanashi K, Higashida A, Hasegawa K, Ono Y, Oikawa N, Mio T Mol Cancer Ther. 2018 Dec;17(12):2519-2529. doi: 10.1158/1535-7163.MCT-17-1180., Epub 2018 Sep 21. PMID:30242093<ref>PMID:30242093</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 5wr7" style="background-color:#fffaf0;"></div>
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Receptor protein-tyrosine kinase]]		[[Category: Receptor protein-tyrosine kinase]]
	[[Category: Augustin, M]]		[[Category: Augustin, M]]

OCA at 07:18, 6 December 2017

OCA — Wed, 06 Dec 2017 07:18:32 GMT

←Older revision		Revision as of 07:18, 6 December 2017
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 5wr7 is ~~ON HOLD until Nov 30 2018~~	+	==Crystal structure of Trk-A complexed with a selective inhibitor CH7057288==
-		+	<StructureSection load='5wr7' size='340' side='right' caption='[[5wr7]], [[Resolution\|resolution]] 2.76Å' scene=''>
-	~~Authors~~: ~~Tanaka~~, H., ~~Blaesse~~, M., ~~Augustin~~, M., ~~Goesser, C~~.	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>[[5wr7]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WR7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5WR7 FirstGlance]. <br>
-	~~Description~~: ~~Crystal structure~~ of ~~Trk~~-~~A complexed~~ with a ~~selective inhibitor CH7057288~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=RCH:N-tert-butyl-2-[2-[6,6-dimethyl-8-(methylsulfonylamino)-11-oxidanylidene-naphtho[2,3-b][1]benzofuran-3-yl]ethynyl]-6-methyl-pyridine-4-carboxamide'>RCH</scene></td></tr>
-	[[~~Category~~: ~~Unreleased Structures~~]]	+	<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></td></tr>
-	[[~~Category~~: ~~Tanaka, H~~]]	+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></td></tr>
-	[[Category: ~~Goesser, C~~]]	+	<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=5wr7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wr7 OCA], [http://pdbe.org/5wr7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5wr7 RCSB], [http://www.ebi.ac.uk/pdbsum/5wr7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5wr7 ProSAT]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/NTRK1_HUMAN NTRK1_HUMAN]] Defects in NTRK1 are a cause of congenital insensitivity to pain with anhidrosis (CIPA) [MIM:[http://omim.org/entry/256800 256800]]. CIPA is characterized by a congenital insensitivity to pain, anhidrosis (absence of sweating), absence of reaction to noxious stimuli, self-mutilating behavior, and mental retardation. This rare autosomal recessive disorder is also known as congenital sensory neuropathy with anhidrosis or hereditary sensory and autonomic neuropathy type IV or familial dysautonomia type II.<ref>PMID:8696348</ref> <ref>PMID:10090906</ref> <ref>PMID:10330344</ref> <ref>PMID:10233776</ref> <ref>PMID:10861667</ref> <ref>PMID:10982191</ref> <ref>PMID:10567924</ref> <ref>PMID:11310631</ref> <ref>PMID:11159935</ref> <ref>PMID:22302274</ref> Defects in NTRK1 are a cause of thyroid papillary carcinoma (TPC) [MIM:[http://omim.org/entry/188550 188550]]. TPC is a common tumor of the thyroid that typically arises as an irregular, solid or cystic mass from otherwise normal thyroid tissue. Papillary carcinomas are malignant neoplasm characterized by the formation of numerous, irregular, finger-like projections of fibrous stroma that is covered with a surface layer of neoplastic epithelial cells. Note=Chromosomal aberrations involving NTRK1 are found in thyroid papillary carcinomas. Translocation t(1;3)(q21;q11) with TFG generates the TRKT3 (TRK-T3) transcript by fusing TFG to the 3'-end of NTRK1; a rearrangement with TPM3 generates the TRK transcript by fusing TPM3 to the 3'-end of NTRK1; an intrachromosomal rearrangement that links the protein kinase domain of NTRK1 to the 5'-end of the TPR gene forms the fusion protein TRK-T1. TRK-T1 is a 55 kDa protein reacting with antibodies against the C-terminus of the NTRK1 protein.
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/NTRK1_HUMAN NTRK1_HUMAN]] Receptor tyrosine kinase involved in the development and the maturation of the central and peripheral nervous systems through regulation of proliferation, differentiation and survival of sympathetic and nervous neurons. High affinity receptor for NGF which is its primary ligand, it can also bind and be activated by NTF3/neurotrophin-3. However, NTF3 only supports axonal extension through NTRK1 but has no effect on neuron survival. Upon dimeric NGF ligand-binding, undergoes homodimerization, autophosphorylation and activation. Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades driving cell survival and differentiation. Through SHC1 and FRS2 activates a GRB2-Ras-MAPK cascade that regulates cell differentiation and survival. Through PLCG1 controls NF-Kappa-B activation and the transcription of genes involved in cell survival. Through SHC1 and SH2B1 controls a Ras-PI3 kinase-AKT1 signaling cascade that is also regulating survival. In absence of ligand and activation, may promote cell death, making the survival of neurons dependent on trophic factors.<ref>PMID:1850821</ref> <ref>PMID:1849459</ref> <ref>PMID:8325889</ref> <ref>PMID:8155326</ref> <ref>PMID:11244088</ref> <ref>PMID:15488758</ref> Isoform TrkA-III is resistant to NGF, constitutively activates AKT1 and NF-kappa-B and is unable to activate the Ras-MAPK signaling cascade. Antagonizes the anti-proliferative NGF-NTRK1 signaling that promotes neuronal precursors differentiation. Isoform TrkA-III promotes angiogenesis and has oncogenic activity when overexpressed.<ref>PMID:1850821</ref> <ref>PMID:1849459</ref> <ref>PMID:8325889</ref> <ref>PMID:8155326</ref> <ref>PMID:11244088</ref> <ref>PMID:15488758</ref>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Receptor protein-tyrosine kinase]]
	[[Category: Augustin, M]]		[[Category: Augustin, M]]
	[[Category: Blaesse, M]]		[[Category: Blaesse, M]]
		+	[[Category: Goesser, C]]
		+	[[Category: Tanaka, H]]
		+	[[Category: High affinity nerve growth factor receptor]]
		+	[[Category: Kinase domain]]
		+	[[Category: Proteros biostructures gmbh]]
		+	[[Category: Transferase-transferase inhibitor complex]]
		+	[[Category: Trk-a]]

OCA at 15:05, 27 September 2017

OCA — Wed, 27 Sep 2017 15:05:16 GMT

←Older revision		Revision as of 15:05, 27 September 2017
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	[[Category: Tanaka, H]]		[[Category: Tanaka, H]]
	[[Category: Goesser, C]]		[[Category: Goesser, C]]
-	[[Category: Blaesse, M]]
	[[Category: Augustin, M]]		[[Category: Augustin, M]]
		+	[[Category: Blaesse, M]]

OCA at 19:48, 15 March 2017

OCA — Wed, 15 Mar 2017 19:48:01 GMT

←Older revision		Revision as of 19:48, 15 March 2017
Line 9:		Line 9:
	[[Category: Tanaka, H]]		[[Category: Tanaka, H]]
	[[Category: Goesser, C]]		[[Category: Goesser, C]]
-	[[Category: Augustin, M]]
	[[Category: Blaesse, M]]		[[Category: Blaesse, M]]
		+	[[Category: Augustin, M]]

OCA at 20:37, 22 December 2016

OCA — Thu, 22 Dec 2016 20:37:19 GMT

←Older revision		Revision as of 20:37, 22 December 2016
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 5wr7 is ON HOLD	+	The entry 5wr7 is ON HOLD until Nov 30 2018

	Authors: Tanaka, H., Blaesse, M., Augustin, M., Goesser, C.		Authors: Tanaka, H., Blaesse, M., Augustin, M., Goesser, C.

OCA: Protected "5wr7" [edit=sysop:move=sysop]

OCA — Fri, 09 Dec 2016 18:19:04 GMT

Protected "5wr7" [edit=sysop:move=sysop]

←Older revision

Revision as of 18:19, 9 December 2016

OCA: New page: '''Unreleased structure''' The entry 5wr7 is ON HOLD Authors: Tanaka, H., Blaesse, M., Augustin, M., Goesser, C. Description: Crystal structure of Trk-A complexed with a selective inhi...

OCA — Fri, 09 Dec 2016 18:19:03 GMT

New page: '''Unreleased structure''' The entry 5wr7 is ON HOLD Authors: Tanaka, H., Blaesse, M., Augustin, M., Goesser, C. Description: Crystal structure of Trk-A complexed with a selective inhi...

New page

'''Unreleased structure'''

The entry 5wr7 is ON HOLD

Authors: Tanaka, H., Blaesse, M., Augustin, M., Goesser, C.

Description: Crystal structure of Trk-A complexed with a selective inhibitor CH7057288
[[Category: Unreleased Structures]]
[[Category: Tanaka, H]]
[[Category: Goesser, C]]
[[Category: Augustin, M]]
[[Category: Blaesse, M]]