7vko - Revision history

OCA at 17:27, 29 November 2023

OCA — Wed, 29 Nov 2023 17:27:36 GMT

←Older revision		Revision as of 17:27, 29 November 2023
Line 3:		Line 3:
	<StructureSection load='7vko' size='340' side='right'caption='[[7vko]], [[Resolution\|resolution]] 2.90Å' scene=''>		<StructureSection load='7vko' size='340' side='right'caption='[[7vko]], [[Resolution\|resolution]] 2.90Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[7vko]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7VKO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7VKO FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7vko]] 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=7VKO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7VKO FirstGlance]. <br>
-	</td></tr><tr id='~~ligand~~'><td class="sblockLbl"><b>[[~~Ligand~~\|~~Ligands~~:]]</b></td><td class="sblockDat" id="~~ligandDat~~">~~<scene name='pdbligand=7GI:Repotrectinib'>7GI</scene>~~, ~~<scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>~~</td></tr>	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 2.9Å</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-tyrosine_kinase Receptor protein-tyrosine kinase]~~, ~~with EC number [https~~:~~//www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1]~~ </~~span~~></td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7GI:Repotrectinib'>7GI</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=7vko FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7vko OCA], [https://pdbe.org/7vko PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7vko RCSB], [https://www.ebi.ac.uk/pdbsum/7vko PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7vko 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=7vko FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7vko OCA], [https://pdbe.org/7vko PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7vko RCSB], [https://www.ebi.ac.uk/pdbsum/7vko PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7vko ProSAT]</span></td></tr>
	</table>		</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;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
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	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Receptor protein-tyrosine kinase]]~~	+	[[Category: Besse B]]
-	[[Category: Besse, B]]	+	[[Category: Chen X]]
-	[[Category: Chen, X]]	+	[[Category: Deng W]]
-	[[Category: Deng, W]]	+	[[Category: Drilon A]]
-	[[Category: Drilon, A]]	+	[[Category: Graber A]]
-	[[Category: Graber, A]]	+	[[Category: Murray BW]]
-	[[Category: Murray~~, B W~~]]	+	[[Category: Reich SH]]
-	[[Category: Reich~~, S H~~]]	+	[[Category: Rogers E]]
-	[[Category: Rogers, E]]	+	[[Category: Solomon B]]
-	[[Category: Solomon, B]]	+	[[Category: Sprengeler PA]]
-	[[Category: Sprengeler~~, P A~~]]	+	[[Category: Stopatschinskaja S]]
-	[[Category: Stopatschinskaja, S]]	+	[[Category: Zhai D]]
-	[[Category: Zhai, D]]	+	[[Category: Zhang X]]
-	[[Category: Zhang, X]]	+
-	~~[[Category: Drug resistance]]~~	+
-	~~[[Category: Macrocyclic inhibitor]]~~	+
-	~~[[Category: Ntrk]]~~	+
-	~~[[Category: Repotrectinib]]~~	+
-	~~[[Category: Transferase]]~~	+
-	~~[[Category: Trk~~]]	+

OCA at 08:47, 23 February 2022

OCA — Wed, 23 Feb 2022 08:47:40 GMT

←Older revision		Revision as of 08:47, 23 February 2022
Line 1:		Line 1:

	==Crystal structure of TrkA kinase with repotrectinib==		==Crystal structure of TrkA kinase with repotrectinib==
-	<StructureSection load='7vko' size='340' side='right'caption='[[7vko]]' scene=''>	+	<StructureSection load='7vko' size='340' side='right'caption='[[7vko]], [[Resolution\|resolution]] 2.90Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7VKO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7VKO FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7vko]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7VKO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7VKO FirstGlance]. <br>
-	</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=7vko FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7vko OCA], [https://pdbe.org/7vko PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7vko RCSB], [https://www.ebi.ac.uk/pdbsum/7vko PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7vko ProSAT]</span></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7GI:Repotrectinib'>7GI</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=7vko FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7vko OCA], [https://pdbe.org/7vko PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7vko RCSB], [https://www.ebi.ac.uk/pdbsum/7vko PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7vko ProSAT]</span></td></tr>
	</table>		</table>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	NTRK chromosomal rearrangements yield oncogenic TRK fusion proteins that are sensitive to TRK inhibitors (larotrectinib and entrectinib) but often mutate, limiting the durability of response for NTRK (+) patients. Next-generation inhibitors with compact macrocyclic structures (repotrectinib and selitrectinib) were designed to avoid resistance mutations. Head-to-head potency comparisons of TRK inhibitors and molecular characterization of binding interactions are incomplete, obscuring a detailed understanding of how molecular characteristics translate to potency. Larotrectinib, entrectinib, selitrectinib, and repotrectinib were characterized using cellular models of wild-type TRKA/B/C fusions and resistance mutant variants with a subset evaluated in xenograft tumor models. Crystal structures were determined for repotrectinib bound to TRKA (wild-type, solvent-front mutant). TKI-naive and pretreated case studies are presented. Repotrectinib was the most potent inhibitor of wild-type TRKA/B/C fusions and was more potent than selitrectinib against all tested resistance mutations, underscoring the importance of distinct features of the macrocycle structures. Cocrystal structures of repotrectinib with wild-type TRKA and the TRKA(G595R) SFM variant elucidated how differences in macrocyclic inhibitor structure, binding orientation, and conformational flexibility affect potency and mutant selectivity. The SFM crystal structure revealed an unexpected intramolecular arginine sidechain interaction. Repotrectinib caused tumor regression in LMNA-NTRK1 xenograft models harboring GKM, SFM, xDFG, and GKM + SFM compound mutations. Durable responses were observed in TKI-naive and -pretreated patients with NTRK (+) cancers treated with repotrectinib (NCT03093116). This comprehensive analysis of first- and second-generation TRK inhibitors informs the clinical utility, structural determinants of inhibitor potency, and design of new generations of macrocyclic inhibitors.
		+
		+	Molecular Characteristics of Repotrectinib That Enable Potent Inhibition of TRK Fusion Proteins and Resistant Mutations.,Murray BW, Rogers E, Zhai D, Deng W, Chen X, Sprengeler PA, Zhang X, Graber A, Reich SH, Stopatschinskaja S, Solomon B, Besse B, Drilon A Mol Cancer Ther. 2021 Dec;20(12):2446-2456. doi: 10.1158/1535-7163.MCT-21-0632., Epub 2021 Oct 8. PMID:34625502<ref>PMID:34625502</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7vko" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Besse B]]	+	[[Category: Receptor protein-tyrosine kinase]]
-	[[Category: Chen X]]	+	[[Category: Besse, B]]
-	[[Category: Deng W]]	+	[[Category: Chen, X]]
-	[[Category: Drilon A]]	+	[[Category: Deng, W]]
-	[[Category: Graber A]]	+	[[Category: Drilon, A]]
-	[[Category: Murray BW]]	+	[[Category: Graber, A]]
-	[[Category: Reich SH]]	+	[[Category: Murray, B W]]
-	[[Category: Rogers E]]	+	[[Category: Reich, S H]]
-	[[Category: Solomon B]]	+	[[Category: Rogers, E]]
-	[[Category: Sprengeler PA]]	+	[[Category: Solomon, B]]
-	[[Category: Stopatschinskaja S]]	+	[[Category: Sprengeler, P A]]
-	[[Category: Zhai D]]	+	[[Category: Stopatschinskaja, S]]
-	[[Category: Zhang X]]	+	[[Category: Zhai, D]]
		+	[[Category: Zhang, X]]
		+	[[Category: Drug resistance]]
		+	[[Category: Macrocyclic inhibitor]]
		+	[[Category: Ntrk]]
		+	[[Category: Repotrectinib]]
		+	[[Category: Transferase]]
		+	[[Category: Trk]]

OCA at 11:47, 13 October 2021

OCA — Wed, 13 Oct 2021 11:47:58 GMT

←Older revision		Revision as of 11:47, 13 October 2021
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 7vko ~~is ON HOLD~~	+	==Crystal structure of TrkA kinase with repotrectinib==
-		+	<StructureSection load='7vko' size='340' side='right'caption='[[7vko]]' scene=''>
-	~~Authors~~: ~~Murray, B~~.W.~~, Rogers, E~~.~~, Zhai, D~~.~~, Deng, W~~.~~, Chen, X~~.~~, Sprengeler, P~~.A.~~, Zhang, X~~., ~~Graber, A~~.~~, Reich, S~~.H., ~~Stopatschinskaja, S~~., ~~Solomon, B~~., ~~Besse, B~~., ~~Drilon, A~~.	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7VKO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7VKO FirstGlance]. <br>
-	~~Description: Crystal structure of TrkA kinase with repotrectinib~~	+	</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=7vko FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7vko OCA], [https://pdbe.org/7vko PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7vko RCSB], [https://www.ebi.ac.uk/pdbsum/7vko PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7vko ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
-	[[Category: ~~Graber, A~~]]	+	__TOC__
-	[[Category: ~~Rogers, E~~]]	+	</StructureSection>
-	[[Category: ~~Zhang, X~~]]	+	[[Category: Large Structures]]
-	[[Category: ~~Besse, B~~]]	+	[[Category: Besse B]]
-	[[Category: ~~Deng, W~~]]	+	[[Category: Chen X]]
-	[[Category: Murray~~, B.W~~]]	+	[[Category: Deng W]]
-	[[Category: ~~Solomon, B~~]]	+	[[Category: Drilon A]]
-	[[Category: ~~Reich, S.H~~]]	+	[[Category: Graber A]]
-	[[Category: ~~Drilon, A~~]]	+	[[Category: Murray BW]]
-	[[Category: ~~Chen, X~~]]	+	[[Category: Reich SH]]
-	[[Category: ~~Zhai, D~~]]	+	[[Category: Rogers E]]
-	[[Category: ~~Stopatschinskaja, S~~]]	+	[[Category: Solomon B]]
-	[[Category: ~~Sprengeler, P.A~~]]	+	[[Category: Sprengeler PA]]
		+	[[Category: Stopatschinskaja S]]
		+	[[Category: Zhai D]]
		+	[[Category: Zhang X]]

OCA: Protected "7vko" [edit=sysop:move=sysop]

OCA — Wed, 06 Oct 2021 04:26:43 GMT

Protected "7vko" [edit=sysop:move=sysop]

←Older revision

Revision as of 04:26, 6 October 2021

OCA: New page: '''Unreleased structure''' The entry 7vko is ON HOLD Authors: Murray, B.W., Rogers, E., Zhai, D., Deng, W., Chen, X., Sprengeler, P.A., Zhang, X., Graber, A., Reich, S.H., Stopatschinsk...

OCA — Wed, 06 Oct 2021 04:26:42 GMT

New page: '''Unreleased structure''' The entry 7vko is ON HOLD Authors: Murray, B.W., Rogers, E., Zhai, D., Deng, W., Chen, X., Sprengeler, P.A., Zhang, X., Graber, A., Reich, S.H., Stopatschinsk...

New page

'''Unreleased structure'''

The entry 7vko is ON HOLD

Authors: Murray, B.W., Rogers, E., Zhai, D., Deng, W., Chen, X., Sprengeler, P.A., Zhang, X., Graber, A., Reich, S.H., Stopatschinskaja, S., Solomon, B., Besse, B., Drilon, A.

Description: Crystal structure of TrkA kinase with repotrectinib
[[Category: Unreleased Structures]]
[[Category: Graber, A]]
[[Category: Rogers, E]]
[[Category: Zhang, X]]
[[Category: Besse, B]]
[[Category: Deng, W]]
[[Category: Murray, B.W]]
[[Category: Solomon, B]]
[[Category: Reich, S.H]]
[[Category: Drilon, A]]
[[Category: Chen, X]]
[[Category: Zhai, D]]
[[Category: Stopatschinskaja, S]]
[[Category: Sprengeler, P.A]]