7lfs - Revision history

OCA at 15:47, 18 October 2023

OCA — Wed, 18 Oct 2023 15:47:28 GMT

←Older revision		Revision as of 15:47, 18 October 2023
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-	====	+	==Crystal structure of the epidermal growth factor receptor extracellular region with A265V mutation in complex with epiregulin==
-	<StructureSection load='7lfs' size='340' side='right'caption='[[7lfs]]' scene=''>	+	<StructureSection load='7lfs' size='340' side='right'caption='[[7lfs]], [[Resolution\|resolution]] 3.50Å' 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= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7lfs]] is a 8 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=7LFS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LFS 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=7lfs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lfs OCA], [https://pdbe.org/7lfs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lfs RCSB], [https://www.ebi.ac.uk/pdbsum/7lfs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lfs ProSAT]</span></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]] 3.5Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=7lfs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lfs OCA], [https://pdbe.org/7lfs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lfs RCSB], [https://www.ebi.ac.uk/pdbsum/7lfs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lfs ProSAT]</span></td></tr>
	</table>		</table>
		+	== Disease ==
		+	[https://www.uniprot.org/uniprot/EGFR_HUMAN EGFR_HUMAN] Defects in EGFR are associated with lung cancer (LNCR) [MIM:[https://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 ==
		+	[https://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 ==
		+	The epidermal growth factor receptor (EGFR) is frequently mutated in human cancer(1,2), and is an important therapeutic target. EGFR inhibitors have been successful in lung cancer, where mutations in the intracellular tyrosine kinase domain activate the receptor(1), but not in glioblastoma multiforme (GBM)(3), where mutations occur exclusively in the extracellular region. Here we show that common extracellular GBM mutations prevent EGFR from discriminating between its activating ligands(4). Different growth factor ligands stabilize distinct EGFR dimer structures(5) that signal with different kinetics to specify or bias outcome(5,6). EGF itself induces strong symmetric dimers that signal transiently to promote proliferation. Epiregulin (EREG) induces much weaker asymmetric dimers that drive sustained signalling and differentiation(5). GBM mutations reduce the ability of EGFR to distinguish EREG from EGF in cellular assays, and allow EGFR to form strong (EGF-like) dimers in response to EREG and other low-affinity ligands. Using X-ray crystallography, we further show that the R84K GBM mutation symmetrizes EREG-driven extracellular dimers so that they resemble dimers normally seen with EGF. By contrast, a second GBM mutation, A265V, remodels key dimerization contacts to strengthen asymmetric EREG-driven dimers. Our results argue for an important role of altered ligand discrimination by EGFR in GBM, with potential implications for therapeutic targeting.
		+
		+	Glioblastoma mutations alter EGFR dimer structure to prevent ligand bias.,Hu C, Leche CA 2nd, Kiyatkin A, Yu Z, Stayrook SE, Ferguson KM, Lemmon MA Nature. 2022 Feb;602(7897):518-522. doi: 10.1038/s41586-021-04393-3. Epub 2022 , Feb 9. PMID:35140400<ref>PMID:35140400</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7lfs" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Epidermal growth factor receptor 3D structures\|Epidermal growth factor receptor 3D structures]]
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: ~~Z-disk~~]]	+	[[Category: Ferguson KM]]
		+	[[Category: Hu C]]
		+	[[Category: Leche II CA]]
		+	[[Category: Lemmon MA]]
		+	[[Category: Stayrook SE]]

OCA at 13:36, 17 November 2021

OCA — Wed, 17 Nov 2021 13:36:49 GMT

←Older revision		Revision as of 13:36, 17 November 2021
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-	'''Unreleased structure'''

-	~~The entry~~ 7lfs ~~is ON HOLD until Paper Publication~~	+	====
-		+	<StructureSection load='7lfs' size='340' side='right'caption='[[7lfs]]' scene=''>
-	~~Authors~~: ~~Hu, C~~.~~, Leche II, C~~.A.~~, Stayrook, S~~.E.~~, Ferguson, K~~.~~M., Lemmon, M.A~~.	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br>
-	~~Description~~: ~~Crystal structure of the epidermal growth factor receptor extracellular region with A265V mutation in complex with epiregulin~~	+	</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=7lfs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lfs OCA], [https://pdbe.org/7lfs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lfs RCSB], [https://www.ebi.ac.uk/pdbsum/7lfs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lfs ProSAT]</span></td></tr>
-	[~~[Category~~: ~~Unreleased Structures~~]]	+	</table>
-	[[~~Category~~: ~~Stayrook, S~~.E]]	+	__TOC__
-	[~~[Category~~: ~~Leche Ii~~, C.A]]	+	</StructureSection>
-	[~~[Category~~: ~~Ferguson~~, K.M]]	+	[[Category: Large Structures]]
-	[[Category: ~~Lemmon, M.A~~]]	+	[[Category: Z-disk]]
-	[[Category: ~~Hu, C~~]]	+

OCA at 05:37, 24 February 2021

OCA — Wed, 24 Feb 2021 05:37:07 GMT

←Older revision		Revision as of 05:37, 24 February 2021
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7lfs is ON HOLD	+	The entry 7lfs is ON HOLD until Paper Publication

	Authors: Hu, C., Leche II, C.A., Stayrook, S.E., Ferguson, K.M., Lemmon, M.A.		Authors: Hu, C., Leche II, C.A., Stayrook, S.E., Ferguson, K.M., Lemmon, M.A.
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	Description: Crystal structure of the epidermal growth factor receptor extracellular region with A265V mutation in complex with epiregulin		Description: Crystal structure of the epidermal growth factor receptor extracellular region with A265V mutation in complex with epiregulin
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
-	[[Category: Ferguson, K.M]]
	[[Category: Stayrook, S.E]]		[[Category: Stayrook, S.E]]
	[[Category: Leche Ii, C.A]]		[[Category: Leche Ii, C.A]]
		+	[[Category: Ferguson, K.M]]
	[[Category: Lemmon, M.A]]		[[Category: Lemmon, M.A]]
	[[Category: Hu, C]]		[[Category: Hu, C]]

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

OCA — Wed, 27 Jan 2021 06:48:12 GMT

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

←Older revision

Revision as of 06:48, 27 January 2021

OCA: New page: '''Unreleased structure''' The entry 7lfs is ON HOLD Authors: Hu, C., Leche II, C.A., Stayrook, S.E., Ferguson, K.M., Lemmon, M.A. Description: Crystal structure of the epidermal growt...

OCA — Wed, 27 Jan 2021 06:48:11 GMT

New page: '''Unreleased structure''' The entry 7lfs is ON HOLD Authors: Hu, C., Leche II, C.A., Stayrook, S.E., Ferguson, K.M., Lemmon, M.A. Description: Crystal structure of the epidermal growt...

New page

'''Unreleased structure'''

The entry 7lfs is ON HOLD

Authors: Hu, C., Leche II, C.A., Stayrook, S.E., Ferguson, K.M., Lemmon, M.A.

Description: Crystal structure of the epidermal growth factor receptor extracellular region with A265V mutation in complex with epiregulin
[[Category: Unreleased Structures]]
[[Category: Ferguson, K.M]]
[[Category: Stayrook, S.E]]
[[Category: Leche Ii, C.A]]
[[Category: Lemmon, M.A]]
[[Category: Hu, C]]