6jwl - Revision history

OCA at 07:30, 4 November 2020

2020-11-04T07:30:19Z

←Older revision		Revision as of 07:30, 4 November 2020
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	== Function ==		== Function ==
	[[http://www.uniprot.org/uniprot/EGFR_HUMAN EGFR_HUMAN]] Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses. Known ligands include EGF, TGFA/TGF-alpha, amphiregulin, epigen/EPGN, BTC/betacellulin, epiregulin/EREG and HBEGF/heparin-binding EGF. Ligand binding triggers receptor homo- and/or heterodimerization and autophosphorylation on key cytoplasmic residues. The phosphorylated receptor recruits adapter proteins like GRB2 which in turn activates complex downstream signaling cascades. Activates at least 4 major downstream signaling cascades including the RAS-RAF-MEK-ERK, PI3 kinase-AKT, PLCgamma-PKC and STATs modules. May also activate the NF-kappa-B signaling cascade. Also directly phosphorylates other proteins like RGS16, activating its GTPase activity and probably coupling the EGF receptor signaling to the G protein-coupled receptor signaling. Also phosphorylates MUC1 and increases its interaction with SRC and CTNNB1/beta-catenin.<ref>PMID:7657591</ref> <ref>PMID:11602604</ref> <ref>PMID:12873986</ref> <ref>PMID:10805725</ref> <ref>PMID:11116146</ref> <ref>PMID:11483589</ref> <ref>PMID:17115032</ref> <ref>PMID:21258366</ref> <ref>PMID:12297050</ref> <ref>PMID:12620237</ref> <ref>PMID:15374980</ref> <ref>PMID:19560417</ref> <ref>PMID:20837704</ref> Isoform 2 may act as an antagonist of EGF action.<ref>PMID:7657591</ref> <ref>PMID:11602604</ref> <ref>PMID:12873986</ref> <ref>PMID:10805725</ref> <ref>PMID:11116146</ref> <ref>PMID:11483589</ref> <ref>PMID:17115032</ref> <ref>PMID:21258366</ref> <ref>PMID:12297050</ref> <ref>PMID:12620237</ref> <ref>PMID:15374980</ref> <ref>PMID:19560417</ref> <ref>PMID:20837704</ref>		[[http://www.uniprot.org/uniprot/EGFR_HUMAN EGFR_HUMAN]] Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses. Known ligands include EGF, TGFA/TGF-alpha, amphiregulin, epigen/EPGN, BTC/betacellulin, epiregulin/EREG and HBEGF/heparin-binding EGF. Ligand binding triggers receptor homo- and/or heterodimerization and autophosphorylation on key cytoplasmic residues. The phosphorylated receptor recruits adapter proteins like GRB2 which in turn activates complex downstream signaling cascades. Activates at least 4 major downstream signaling cascades including the RAS-RAF-MEK-ERK, PI3 kinase-AKT, PLCgamma-PKC and STATs modules. May also activate the NF-kappa-B signaling cascade. Also directly phosphorylates other proteins like RGS16, activating its GTPase activity and probably coupling the EGF receptor signaling to the G protein-coupled receptor signaling. Also phosphorylates MUC1 and increases its interaction with SRC and CTNNB1/beta-catenin.<ref>PMID:7657591</ref> <ref>PMID:11602604</ref> <ref>PMID:12873986</ref> <ref>PMID:10805725</ref> <ref>PMID:11116146</ref> <ref>PMID:11483589</ref> <ref>PMID:17115032</ref> <ref>PMID:21258366</ref> <ref>PMID:12297050</ref> <ref>PMID:12620237</ref> <ref>PMID:15374980</ref> <ref>PMID:19560417</ref> <ref>PMID:20837704</ref> Isoform 2 may act as an antagonist of EGF action.<ref>PMID:7657591</ref> <ref>PMID:11602604</ref> <ref>PMID:12873986</ref> <ref>PMID:10805725</ref> <ref>PMID:11116146</ref> <ref>PMID:11483589</ref> <ref>PMID:17115032</ref> <ref>PMID:21258366</ref> <ref>PMID:12297050</ref> <ref>PMID:12620237</ref> <ref>PMID:15374980</ref> <ref>PMID:19560417</ref> <ref>PMID:20837704</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	AZD9291 (Osimertinib) is highly effective in treating EGFR-mutated non-small-cell lung cancers (NSCLCs) with T790M-mediated drug resistance. Despite the remarkable success of AZD9291, its binding pose with EGFR T790M remains unclear. Here, we report unbiased, atomic-level molecular dynamics (MD) simulations in which spontaneous association of AZD9291 with EGFR kinases having WT and T790M mutant gatekeepers was observed. Simulation-generated structural models suggest that the binding pose of AZD9291 with T790M differs from its binding pose with the WT, and that AZD9291 interacts extensively with the gatekeeper residue (Met 790) in T790M but not with Thr 790 in the WT, which explains why AZD9291 binds T790M with higher affinity. The MD simulation-generated models were confirmed by experimentally determined EGFR/T790M complex crystal structures. This work may facilitate the rational design of drugs that can overcome resistance mutations to AZD9291, and more generally it suggests the potential of using unbiased MD simulation to elucidate small-molecule binding poses.
		+
		+	Structural Basis of AZD9291 Selectivity for EGFR T790M.,Yan XE, Ayaz P, Zhu SJ, Zhao P, Liang L, Zhang CH, Wu YC, Li JL, Choi HG, Huang X, Shan Y, Shaw DE, Yun CH J Med Chem. 2020 Aug 13;63(15):8502-8511. doi: 10.1021/acs.jmedchem.0c00891. Epub, 2020 Aug 3. PMID:32672461<ref>PMID:32672461</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 6jwl" style="background-color:#fffaf0;"></div>
	== References ==		== References ==
	<references/>		<references/>

OCA at 09:47, 9 September 2020

2020-09-09T09:47:34Z

←Older revision		Revision as of 09:47, 9 September 2020
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	==Crystal structure of EGFR 696-1022 L858R in complex with AZD9291==		==Crystal structure of EGFR 696-1022 L858R in complex with AZD9291==
-	<StructureSection load='6jwl' size='340' side='right'caption='[[6jwl]]' scene=''>	+	<StructureSection load='6jwl' size='340' side='right'caption='[[6jwl]], [[Resolution\|resolution]] 2.55Å' 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=6JWL OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6JWL FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6jwl]] 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=6JWL OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6JWL FirstGlance]. <br>
-	</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6jwl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jwl OCA], [http://pdbe.org/6jwl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6jwl RCSB], [http://www.ebi.ac.uk/pdbsum/6jwl PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6jwl 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=YY3:N-(2-{[2-(DIMETHYLAMINO)ETHYL](METHYL)AMINO}-4-METHOXY-5-{[4-(1-METHYL-1H-INDOL-3-YL)PYRIMIDIN-2-YL]AMINO}PHENYL)PROP-2-ENAMIDE'>YY3</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">EGFR, ERBB, ERBB1, HER1 ([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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6jwl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jwl OCA], [http://pdbe.org/6jwl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6jwl RCSB], [http://www.ebi.ac.uk/pdbsum/6jwl PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6jwl ProSAT]</span></td></tr>
	</table>		</table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/EGFR_HUMAN EGFR_HUMAN]] Defects in EGFR are associated with lung cancer (LNCR) [MIM:[http://omim.org/entry/211980 211980]]. LNCR is a common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis.
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/EGFR_HUMAN EGFR_HUMAN]] Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses. Known ligands include EGF, TGFA/TGF-alpha, amphiregulin, epigen/EPGN, BTC/betacellulin, epiregulin/EREG and HBEGF/heparin-binding EGF. Ligand binding triggers receptor homo- and/or heterodimerization and autophosphorylation on key cytoplasmic residues. The phosphorylated receptor recruits adapter proteins like GRB2 which in turn activates complex downstream signaling cascades. Activates at least 4 major downstream signaling cascades including the RAS-RAF-MEK-ERK, PI3 kinase-AKT, PLCgamma-PKC and STATs modules. May also activate the NF-kappa-B signaling cascade. Also directly phosphorylates other proteins like RGS16, activating its GTPase activity and probably coupling the EGF receptor signaling to the G protein-coupled receptor signaling. Also phosphorylates MUC1 and increases its interaction with SRC and CTNNB1/beta-catenin.<ref>PMID:7657591</ref> <ref>PMID:11602604</ref> <ref>PMID:12873986</ref> <ref>PMID:10805725</ref> <ref>PMID:11116146</ref> <ref>PMID:11483589</ref> <ref>PMID:17115032</ref> <ref>PMID:21258366</ref> <ref>PMID:12297050</ref> <ref>PMID:12620237</ref> <ref>PMID:15374980</ref> <ref>PMID:19560417</ref> <ref>PMID:20837704</ref> Isoform 2 may act as an antagonist of EGF action.<ref>PMID:7657591</ref> <ref>PMID:11602604</ref> <ref>PMID:12873986</ref> <ref>PMID:10805725</ref> <ref>PMID:11116146</ref> <ref>PMID:11483589</ref> <ref>PMID:17115032</ref> <ref>PMID:21258366</ref> <ref>PMID:12297050</ref> <ref>PMID:12620237</ref> <ref>PMID:15374980</ref> <ref>PMID:19560417</ref> <ref>PMID:20837704</ref>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Yan XE]]	+	[[Category: Receptor protein-tyrosine kinase]]
-	[[Category: Yun CH]]	+	[[Category: Yan, X E]]
-	[[Category: Zhu SJ]]	+	[[Category: Yun, C H]]
		+	[[Category: Zhu, S J]]
		+	[[Category: Complex]]
		+	[[Category: Egfr]]
		+	[[Category: Inhibitor]]
		+	[[Category: Oncoprotein]]
		+	[[Category: Transferase]]

OCA at 05:39, 22 April 2020

2020-04-22T05:39:42Z

←Older revision		Revision as of 05:39, 22 April 2020
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6jwl ~~is ON HOLD until Paper Publication~~	+	==Crystal structure of EGFR 696-1022 L858R in complex with AZD9291==
-		+	<StructureSection load='6jwl' size='340' side='right'caption='[[6jwl]]' scene=''>
-	~~Authors~~: ~~Yun~~, C.H., ~~Zhu~~, S.J., ~~Yan~~, X.E.	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6JWL OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6JWL FirstGlance]. <br>
-	~~Description: Crystal structure of EGFR 696-1022 L858R in complex with AZD9291~~	+	</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6jwl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jwl OCA], [http://pdbe.org/6jwl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6jwl RCSB], [http://www.ebi.ac.uk/pdbsum/6jwl PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6jwl ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
-	[[Category: ~~Zhu, S.J~~]]	+	__TOC__
-	[[Category: Yun~~, C.H~~]]	+	</StructureSection>
-	[[Category: ~~Yan, X.E~~]]	+	[[Category: Large Structures]]
		+	[[Category: Yan XE]]
		+	[[Category: Yun CH]]
		+	[[Category: Zhu SJ]]

OCA at 04:21, 29 May 2019

2019-05-29T04:21:27Z

←Older revision		Revision as of 04:21, 29 May 2019
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6jwl is ON HOLD	+	The entry 6jwl is ON HOLD until Paper Publication

	Authors: Yun, C.H., Zhu, S.J., Yan, X.E.		Authors: Yun, C.H., Zhu, S.J., Yan, X.E.
Line 7:		Line 7:
	Description: Crystal structure of EGFR 696-1022 L858R in complex with AZD9291		Description: Crystal structure of EGFR 696-1022 L858R in complex with AZD9291
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
-	[[Category: Yan, X.E]]
	[[Category: Zhu, S.J]]		[[Category: Zhu, S.J]]
	[[Category: Yun, C.H]]		[[Category: Yun, C.H]]
		+	[[Category: Yan, X.E]]

OCA: Protected "6jwl" [edit=sysop:move=sysop]

2019-05-01T06:57:14Z

Protected "6jwl" [edit=sysop:move=sysop]

←Older revision

Revision as of 06:57, 1 May 2019

OCA: New page: '''Unreleased structure''' The entry 6jwl is ON HOLD Authors: Yun, C.H., Zhu, S.J., Yan, X.E. Description: Crystal structure of EGFR 696-1022 L858R in complex with AZD9291 [[Category: ...

2019-05-01T06:57:12Z

New page: '''Unreleased structure''' The entry 6jwl is ON HOLD Authors: Yun, C.H., Zhu, S.J., Yan, X.E. Description: Crystal structure of EGFR 696-1022 L858R in complex with AZD9291 [[Category: ...

New page

'''Unreleased structure'''

The entry 6jwl is ON HOLD

Authors: Yun, C.H., Zhu, S.J., Yan, X.E.

Description: Crystal structure of EGFR 696-1022 L858R in complex with AZD9291
[[Category: Unreleased Structures]]
[[Category: Yan, X.E]]
[[Category: Zhu, S.J]]
[[Category: Yun, C.H]]