4g5p - Revision history

OCA at 20:26, 19 October 2022

OCA — Wed, 19 Oct 2022 20:26:06 GMT

←Older revision		Revision as of 20:26, 19 October 2022
Line 3:		Line 3:
	<StructureSection load='4g5p' size='340' side='right'caption='[[4g5p]], [[Resolution\|resolution]] 3.17Å' scene=''>		<StructureSection load='4g5p' size='340' side='right'caption='[[4g5p]], [[Resolution\|resolution]] 3.17Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4g5p]] is a 2 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=4G5P OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4G5P FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4g5p]] is a 2 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=4G5P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4G5P FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0WN:N-{4-[(3-CHLORO-4-FLUOROPHENYL)AMINO]-7-[(3S)-TETRAHYDROFURAN-3-YLOXY]QUINAZOLIN-6-YL}-4-(DIMETHYLAMINO)BUTANAMIDE'>0WN</scene~~></td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0WN:N-{4-[(3-CHLORO-4-FLUOROPHENYL)AMINO]-7-[(3S)-TETRAHYDROFURAN-3-YLOXY]QUINAZOLIN-6-YL}-4-(DIMETHYLAMINO)BUTANAMIDE'>0WN</scene></td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4g5j\|4g5j]]</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=4g5p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4g5p OCA], [https://pdbe.org/4g5p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4g5p RCSB], [https://www.ebi.ac.uk/pdbsum/4g5p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4g5p ProSAT]</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=4g5p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4g5p OCA], [~~http~~://pdbe.org/4g5p PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4g5p RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4g5p PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4g5p ProSAT]</span></td></tr>	+
	</table>		</table>
	== Disease ==		== 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.	+	[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 ==		== 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>	+	[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;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
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	==See Also==		==See Also==
-	*[[Epidermal ~~Growth Factor Receptor~~\|Epidermal ~~Growth Factor Receptor~~]]	+	*[[Epidermal growth factor receptor 3D structures\|Epidermal growth factor receptor 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Receptor protein-tyrosine kinase]]~~	+	[[Category: Adolf GR]]
-	[[Category: Adolf~~, G R~~]]	+	[[Category: Bader G]]
-	[[Category: Bader, G]]	+	[[Category: Dahl G]]
-	[[Category: Dahl, G]]	+	[[Category: Haaksma E]]
-	[[Category: Haaksma, E]]	+	[[Category: Himmelsbach F]]
-	[[Category: Himmelsbach, F]]	+	[[Category: Klein C]]
-	[[Category: Klein, C]]	+	[[Category: Kraemer O]]
-	[[Category: Kraemer, O]]	+	[[Category: Sanderson M]]
-	[[Category: Sanderson, M]]	+	[[Category: Solca F]]
-	[[Category: Solca, F]]	+	[[Category: Zoephel A]]
-	[[Category: Zoephel, A]]	+
-	~~[[Category: Egf receptor kinase mutant t790m]]~~	+
-	~~[[Category: Transferase-transferase inhibitor complex~~]]	+

OCA at 08:03, 27 March 2019

OCA — Wed, 27 Mar 2019 08:03:03 GMT

←Older revision		Revision as of 08:03, 27 March 2019
Line 1:		Line 1:

	==Crystal structure of EGFR kinase T790M in complex with BIBW2992==		==Crystal structure of EGFR kinase T790M in complex with BIBW2992==
-	<StructureSection load='4g5p' size='340' side='right' caption='[[4g5p]], [[Resolution\|resolution]] 3.17Å' scene=''>	+	<StructureSection load='4g5p' size='340' side='right'caption='[[4g5p]], [[Resolution\|resolution]] 3.17Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4g5p]] is a 2 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=4G5P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4G5P FirstGlance]. <br>		<table><tr><td colspan='2'>[[4g5p]] is a 2 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=4G5P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4G5P FirstGlance]. <br>
Line 30:		Line 30:
	</StructureSection>		</StructureSection>
	[[Category: Human]]		[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Receptor protein-tyrosine kinase]]		[[Category: Receptor protein-tyrosine kinase]]
	[[Category: Adolf, G R]]		[[Category: Adolf, G R]]

OCA at 03:25, 5 August 2016

OCA — Fri, 05 Aug 2016 03:25:26 GMT

←Older revision		Revision as of 03:25, 5 August 2016
Line 1:		Line 1:
		+
	==Crystal structure of EGFR kinase T790M in complex with BIBW2992==		==Crystal structure of EGFR kinase T790M in complex with BIBW2992==
	<StructureSection load='4g5p' size='340' side='right' caption='[[4g5p]], [[Resolution\|resolution]] 3.17Å' scene=''>		<StructureSection load='4g5p' size='340' side='right' caption='[[4g5p]], [[Resolution\|resolution]] 3.17Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4g5p]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/~~Homo_sapiens Homo sapiens~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4G5P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4G5P FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4g5p]] is a 2 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=4G5P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4G5P FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0WN:N-{4-[(3-CHLORO-4-FLUOROPHENYL)AMINO]-7-[(3S)-TETRAHYDROFURAN-3-YLOXY]QUINAZOLIN-6-YL}-4-(DIMETHYLAMINO)BUTANAMIDE'>0WN</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0WN:N-{4-[(3-CHLORO-4-FLUOROPHENYL)AMINO]-7-[(3S)-TETRAHYDROFURAN-3-YLOXY]QUINAZOLIN-6-YL}-4-(DIMETHYLAMINO)BUTANAMIDE'>0WN</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4g5j\|4g5j]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4g5j\|4g5j]]</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=4g5p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4g5p OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4g5p RCSB], [http://www.ebi.ac.uk/pdbsum/4g5p PDBsum]</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=4g5p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4g5p OCA], [http://pdbe.org/4g5p PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4g5p RCSB], [http://www.ebi.ac.uk/pdbsum/4g5p PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4g5p ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 20:		Line 21:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
		+	<div class="pdbe-citations 4g5p" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
Line 27:		Line 29:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Homo sapiens~~]]	+	[[Category: Human]]
	[[Category: Receptor protein-tyrosine kinase]]		[[Category: Receptor protein-tyrosine kinase]]
	[[Category: Adolf, G R]]		[[Category: Adolf, G R]]

OCA at 11:32, 21 December 2014

OCA — Sun, 21 Dec 2014 11:32:10 GMT

←Older revision		Revision as of 11:32, 21 December 2014
Line 1:		Line 1:
-	~~{{STRUCTURE_4g5p\| PDB=4g5p \| SCENE= }}~~	+	==Crystal structure of EGFR kinase T790M in complex with BIBW2992==
-	===Crystal structure of EGFR kinase T790M in complex with BIBW2992===	+	<StructureSection load='4g5p' size='340' side='right' caption='[[4g5p]], [[Resolution\|resolution]] 3.17Å' scene=''>
-	{~~{ABSTRACT_PUBMED_22888144}~~}	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>[[4g5p]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4G5P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4G5P FirstGlance]. <br>
-	==Disease==	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0WN:N-{4-[(3-CHLORO-4-FLUOROPHENYL)AMINO]-7-[(3S)-TETRAHYDROFURAN-3-YLOXY]QUINAZOLIN-6-YL}-4-(DIMETHYLAMINO)BUTANAMIDE'>0WN</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4g5j\|4g5j]]</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=4g5p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4g5p OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4g5p RCSB], [http://www.ebi.ac.uk/pdbsum/4g5p PDBsum]</span></td></tr>
		+	</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.		[[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>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Deregulation of the ErbB receptor network is well recognized as an oncogenic driver in epithelial cancers. Several targeted drugs have been developed, including antibodies and small molecule kinase inhibitors, each of them characterized by distinct patterns of ErbB receptor interactions. Understanding the precise pharmacological properties of these compounds is important for optimal use in clinical practice. Afatinib (BIBW 2992) is an ATP-competitive anilinoquinazoline derivative harboring a reactive acrylamide group and was designed to covalently bind and irreversibly block enzymatically active ErbB receptor family members. Here we show by X-ray crystallography the covalent binding of afatinib to wild-type EGFR and by mass spectrometry the covalent interaction with EGFR, EGFRL858R/T790M, HER2 and ErbB-4. Afatinib potently inhibits the enymatic activity of ErbB-4 (EC50 = 1 nM) and the proliferation of cancer cell lines driven by multiple ErbB receptor aberrations at concentrations below 100 nM. BI 37781, a close analog of afatinib lacking the acrylamide group and thus incapable of covalent bond formation, had similar potency on cells driven by EGFR or EGFRL858R, but less or no detectable activity on cells expressing EGFRL858R/ T790M HER2 or ErbB-4. These results stress the importance of the acrylamide group and show that afatinib differs from approved ErbB targeting agents by irreversibly inhibiting the kinase activity of all ErbB family members. They provide a mechanistic rationale for the distinct pharmacological features of this compound and explain the clinical activity seen in some patients resistant to antibody or kinase inhibitor therapy due to secondary mutations or ErbB receptor 'reprogramming'.

-	~~==Function==~~	+	Target Binding Properties and Cellular Activity of Afatinib (BIBW 2992), an Irreversible ErbB Family Blocker.,Solca F, Dahl G, Zoephel A, Bader G, Sanderson M, Klein C, Kraemer O, Himmelsbach F, Haaksma E, Adolf GR J Pharmacol Exp Ther. 2012 Aug 10. PMID:22888144<ref>PMID:22888144</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>	+

-	~~==About this Structure==~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[4g5p]] is~~ a ~~2 chain structure with sequence from [http://en~~.~~wikipedia~~.~~org/wiki/Homo_sapiens Homo sapiens]~~. ~~Full crystallographic information is available from [http:~~/~~/oca.weizmann.ac.il/oca-bin/ocashort?id=4G5P OCA].~~	+	</div>

-	==~~Reference~~==	+	==See Also==
-	~~<ref group~~=~~"xtra">PMID:022888144</ref>~~<references ~~group="xtra"~~/><~~references~~/>	+	*[[Epidermal Growth Factor Receptor\|Epidermal Growth Factor Receptor]]
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Receptor protein-tyrosine kinase]]		[[Category: Receptor protein-tyrosine kinase]]
-	[[Category: Adolf, G R.]]	+	[[Category: Adolf, G R]]
-	[[Category: Bader, G.]]	+	[[Category: Bader, G]]
-	[[Category: Dahl, G.]]	+	[[Category: Dahl, G]]
-	[[Category: Haaksma, E.]]	+	[[Category: Haaksma, E]]
-	[[Category: Himmelsbach, F.]]	+	[[Category: Himmelsbach, F]]
-	[[Category: Klein, C.]]	+	[[Category: Klein, C]]
-	[[Category: Kraemer, O.]]	+	[[Category: Kraemer, O]]
-	[[Category: Sanderson, M.]]	+	[[Category: Sanderson, M]]
-	[[Category: Solca, F.]]	+	[[Category: Solca, F]]
-	[[Category: Zoephel, A.]]	+	[[Category: Zoephel, A]]
	[[Category: Egf receptor kinase mutant t790m]]		[[Category: Egf receptor kinase mutant t790m]]
	[[Category: Transferase-transferase inhibitor complex]]		[[Category: Transferase-transferase inhibitor complex]]

OCA at 10:05, 24 March 2013

OCA — Sun, 24 Mar 2013 10:05:34 GMT

←Older revision		Revision as of 10:05, 24 March 2013
Line 1:		Line 1:
-	[[Image:4g5p.png\|left\|200px]]
-
	{{STRUCTURE_4g5p\| PDB=4g5p \| SCENE= }}		{{STRUCTURE_4g5p\| PDB=4g5p \| SCENE= }}
-
	===Crystal structure of EGFR kinase T790M in complex with BIBW2992===		===Crystal structure of EGFR kinase T790M in complex with BIBW2992===
		+	{{ABSTRACT_PUBMED_22888144}}

-	~~{{ABSTRACT_PUBMED_22888144}}~~	+	==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>

	==About this Structure==		==About this Structure==
Line 11:		Line 13:

	==Reference==		==Reference==
-	<ref group="xtra">PMID:022888144</ref><references group="xtra"/>	+	<ref group="xtra">PMID:022888144</ref><references group="xtra"/><references/>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Receptor protein-tyrosine kinase]]		[[Category: Receptor protein-tyrosine kinase]]

OCA at 09:37, 31 October 2012

OCA — Wed, 31 Oct 2012 09:37:00 GMT

←Older revision		Revision as of 09:37, 31 October 2012
Line 1:		Line 1:
-	[[Image:4g5p.~~jpg~~\|left\|200px]]	+	[[Image:4g5p.png\|left\|200px]]

	{{STRUCTURE_4g5p\| PDB=4g5p \| SCENE= }}		{{STRUCTURE_4g5p\| PDB=4g5p \| SCENE= }}

OCA at 05:12, 29 August 2012

OCA — Wed, 29 Aug 2012 05:12:41 GMT

←Older revision		Revision as of 05:12, 29 August 2012
Line 1:		Line 1:
-	~~'''Unreleased structure'''~~	+	[[Image:4g5p.jpg\|left\|200px]]

-	~~The entry~~ 4g5p ~~is ON HOLD~~	+	{{STRUCTURE_4g5p\| PDB=4g5p \| SCENE= }}

-	~~Authors: Solca, F., Dahl, G., Zoephel, A., Bader, G., Sanderson, M., Klein, C., Kraemer, O., Himmelsbach, F., Haaksma, E., Adolf, G.R.~~	+	===Crystal structure of EGFR kinase T790M in complex with BIBW2992===

-	~~Description: Crystal~~ structure ~~of EGFR~~ kinase ~~T790M in~~ complex ~~with BIBW2992~~	+	{{ABSTRACT_PUBMED_22888144}}
		+
		+	==About this Structure==
		+	[[4g5p]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4G5P OCA].
		+
		+	==Reference==
		+	<ref group="xtra">PMID:022888144</ref><references group="xtra"/>
		+	[[Category: Homo sapiens]]
		+	[[Category: Receptor protein-tyrosine kinase]]
		+	[[Category: Adolf, G R.]]
		+	[[Category: Bader, G.]]
		+	[[Category: Dahl, G.]]
		+	[[Category: Haaksma, E.]]
		+	[[Category: Himmelsbach, F.]]
		+	[[Category: Klein, C.]]
		+	[[Category: Kraemer, O.]]
		+	[[Category: Sanderson, M.]]
		+	[[Category: Solca, F.]]
		+	[[Category: Zoephel, A.]]
		+	[[Category: Egf receptor kinase mutant t790m]]
		+	[[Category: Transferase-transferase inhibitor complex]]

OCA: Protected "4g5p" [edit=sysop:move=sysop]

OCA — Wed, 25 Jul 2012 06:53:21 GMT

Protected "4g5p" [edit=sysop:move=sysop]

←Older revision

Revision as of 06:53, 25 July 2012

OCA: New page: '''Unreleased structure''' The entry 4g5p is ON HOLD Authors: Solca, F., Dahl, G., Zoephel, A., Bader, G., Sanderson, M., Klein, C., Kraemer, O., Himmelsbach, F., Haaksma, E., Adolf, G....

OCA — Wed, 25 Jul 2012 06:53:20 GMT

New page: '''Unreleased structure''' The entry 4g5p is ON HOLD Authors: Solca, F., Dahl, G., Zoephel, A., Bader, G., Sanderson, M., Klein, C., Kraemer, O., Himmelsbach, F., Haaksma, E., Adolf, G....

New page

'''Unreleased structure'''

The entry 4g5p is ON HOLD

Authors: Solca, F., Dahl, G., Zoephel, A., Bader, G., Sanderson, M., Klein, C., Kraemer, O., Himmelsbach, F., Haaksma, E., Adolf, G.R.

Description: Crystal structure of EGFR kinase T790M in complex with BIBW2992