OCA at 14:45, 20 September 2023

OCA — Wed, 20 Sep 2023 14:45:36 GMT

←Older revision		Revision as of 14:45, 20 September 2023
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-	'''Unreleased structure'''

-	The ~~entry~~ 8j5w is ~~ON HOLD until Paper~~ Publication	+	==The crystal structure of TrkA(F589L) kinase in complex with N-(3-cyclopropyl-5-((4-methylpiperazin-1-yl)methyl)phenyl)-4^6-methyl-14-oxo-5-oxa-13-aza-1(3,6)-imidazo[1,2-b]pyridazina-4(1,3)-benzenacyclotetradecaphan-2-yne-4^5-carboxamide==
		+	<StructureSection load='8j5w' size='340' side='right'caption='[[8j5w]], [[Resolution\|resolution]] 2.28Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[8j5w]] 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=8J5W OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8J5W FirstGlance]. <br>
		+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 2.2804146Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A4U:N-(3-cyclopropyl-5-((4-methylpiperazin-1-yl)methyl)phenyl)-4^6-methyl-14-oxo-5-oxa-13-aza-1(3,6)-imidazo[1,2-b]pyridazina-4(1,3)-benzenacyclotetradecaphan-2-yne-4^5-carboxamide'>A4U</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=8j5w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8j5w OCA], [https://pdbe.org/8j5w PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8j5w RCSB], [https://www.ebi.ac.uk/pdbsum/8j5w PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8j5w ProSAT]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[https://www.uniprot.org/uniprot/NTRK1_HUMAN NTRK1_HUMAN] Defects in NTRK1 are a cause of congenital insensitivity to pain with anhidrosis (CIPA) [MIM:[https://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:[https://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 ==
		+	[https://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 ==
		+	The solvent-front (SF), gatekeeper, and xDFG motif mutations of tropomyosin receptor kinase (TRK) mediating acquired resistance of larotrectinib and entrectinib represent an unmet clinical need. To date, no effective drugs are being approved to overcome these mutants. Thus, a series of macrocycle compounds were designed and synthesized as new type II TRK inhibitors to combat clinically relevant mutations. The representative compound 10g exhibited excellent potency against wide type TRKA/C, TRKA(G595R), TRKA(G667C)(,) and TRKA(F589L) with IC(50) values of 5.21, 4.51, 6.77, 1.42, and 6.13 nM, respectively, and a good kinome selectivity against 378 kinases. 10g also strongly suppressed the proliferation of Ba/F3 cells transfected with SF, GK, xDFG, and others (Val to Met) single mutants with IC(50) values of 1.43-47.56 nM. Moreover, 10g demonstrated ideal antitumor efficacy in both BaF3-CD74-NTRK1(G595R) and BaF3-CD74-NTRK1(G667C) xenograft models. The study provides a promising lead compound for pan-anticancer drug discovery.

-	~~Authors: Zhang~~, ~~Z.M~~., Wang, Y.J.	+	Structure-Based Optimization of the Third Generation Type II Macrocycle TRK Inhibitors with Improved Activity against Solvent-Front, xDFG, and Gatekeeper Mutations.,Wang Z, Wang J, Wang Y, Xiang S, Zhou H, Song S, Song X, Tu Z, Zhou Y, Ding K, Zhang ZM, Zhang Z, Lu X J Med Chem. 2023 Sep 7. doi: 10.1021/acs.jmedchem.3c00899. PMID:37676745<ref>PMID:37676745</ref>

-	~~Description: The crystal structure~~ of ~~TrkA(F589L) kinase in complex with N~~-(3-~~cyclopropyl-5-((4-methylpiperazin-1-yl)methyl)phenyl)-4^6-methyl-14-oxo-5-oxa-13-aza-1(3,6)-imidazo~~[~~1,2-b~~]~~pyridazina-4(1,3)-benzenacyclotetradecaphan-2-yne-4^5-carboxamide~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
-	[[Category: Wang~~, Y.J~~]]	+	<div class="pdbe-citations 8j5w" style="background-color:#fffaf0;"></div>
-	[[Category: Zhang~~, Z.M~~]]	+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Homo sapiens]]
		+	[[Category: Large Structures]]
		+	[[Category: Wang YJ]]
		+	[[Category: Zhang ZM]]

OCA at 04:14, 6 September 2023

OCA — Wed, 06 Sep 2023 04:14:11 GMT

←Older revision		Revision as of 04:14, 6 September 2023
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 8j5w is ON HOLD	+	The entry 8j5w is ON HOLD until Paper Publication

	Authors: Zhang, Z.M., Wang, Y.J.		Authors: Zhang, Z.M., Wang, Y.J.

OCA at 08:51, 2 August 2023

OCA — Wed, 02 Aug 2023 08:51:24 GMT

←Older revision		Revision as of 08:51, 2 August 2023
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 8j5w is ON HOLD ~~until Paper Publication~~	+	The entry 8j5w is ON HOLD

	Authors: Zhang, Z.M., Wang, Y.J.		Authors: Zhang, Z.M., Wang, Y.J.

OCA at 06:19, 14 June 2023

OCA — Wed, 14 Jun 2023 06:19:23 GMT

←Older revision		Revision as of 06:19, 14 June 2023
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 8j5w is ON HOLD	+	The entry 8j5w is ON HOLD until Paper Publication

	Authors: Zhang, Z.M., Wang, Y.J.		Authors: Zhang, Z.M., Wang, Y.J.

OCA at 05:30, 18 May 2023

OCA — Thu, 18 May 2023 05:30:34 GMT

←Older revision		Revision as of 05:30, 18 May 2023
Line 5:		Line 5:
	Authors: Zhang, Z.M., Wang, Y.J.		Authors: Zhang, Z.M., Wang, Y.J.

-	Description: The crystal structure of TrkA(F589L) kinase in complex with ~~ligand~~	+	Description: The crystal structure of TrkA(F589L) kinase in complex with N-(3-cyclopropyl-5-((4-methylpiperazin-1-yl)methyl)phenyl)-4^6-methyl-14-oxo-5-oxa-13-aza-1(3,6)-imidazo[1,2-b]pyridazina-4(1,3)-benzenacyclotetradecaphan-2-yne-4^5-carboxamide
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
	[[Category: Wang, Y.J]]		[[Category: Wang, Y.J]]
	[[Category: Zhang, Z.M]]		[[Category: Zhang, Z.M]]

OCA: Protected "8j5w" [edit=sysop:move=sysop]

OCA — Wed, 03 May 2023 05:32:02 GMT

Protected "8j5w" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:32, 3 May 2023

OCA: New page: '''Unreleased structure''' The entry 8j5w is ON HOLD Authors: Zhang, Z.M., Wang, Y.J. Description: The crystal structure of TrkA(F589L) kinase in complex with ligand [[Category: Unrele...

OCA — Wed, 03 May 2023 05:32:00 GMT

New page: '''Unreleased structure''' The entry 8j5w is ON HOLD Authors: Zhang, Z.M., Wang, Y.J. Description: The crystal structure of TrkA(F589L) kinase in complex with ligand [[Category: Unrele...

New page

'''Unreleased structure'''

The entry 8j5w is ON HOLD

Authors: Zhang, Z.M., Wang, Y.J.

Description: The crystal structure of TrkA(F589L) kinase in complex with ligand
[[Category: Unreleased Structures]]
[[Category: Wang, Y.J]]
[[Category: Zhang, Z.M]]