4r5s - Revision history

OCA at 10:57, 31 August 2022

OCA — Wed, 31 Aug 2022 10:57:38 GMT

←Older revision		Revision as of 10:57, 31 August 2022
Line 1:		Line 1:

	==Crystal structure of EGFR 696-1022 L858R in complex with FIIN-3==		==Crystal structure of EGFR 696-1022 L858R in complex with FIIN-3==
-	<StructureSection load='4r5s' size='340' side='right'caption='[[4r5s]]~~, [[Resolution\|resolution]] 3.00Å~~' scene=''>	+	<StructureSection load='4r5s' size='340' side='right'caption='[[4r5s]]' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>~~[[4r5s]] is a 1 chain structure.~~ Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4R5S OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4R5S FirstGlance]. <br>	+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4R5S OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4R5S FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FI3:N-[4-({[(2,6-DICHLORO-3,5-DIMETHOXYPHENYL)CARBAMOYL](6-{[4-(4-METHYLPIPERAZIN-1-YL)PHENYL]AMINO}PYRIMIDIN-4-YL)AMINO}METHYL)PHENYL]PROPANAMIDE'>FI3</scene></td></tr>	+	</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=4r5s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r5s OCA], [https://pdbe.org/4r5s PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4r5s RCSB], [https://www.ebi.ac.uk/pdbsum/4r5s PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4r5s ProSAT]</span></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=4r5s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r5s OCA], [https://pdbe.org/4r5s PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4r5s RCSB], [https://www.ebi.ac.uk/pdbsum/4r5s PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4r5s 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 human FGF receptors (FGFRs) play critical roles in various human cancers, and several FGFR inhibitors are currently under clinical investigation. Resistance usually results from selection for mutant kinases that are impervious to the action of the drug or from up-regulation of compensatory signaling pathways. Preclinical studies have demonstrated that resistance to FGFR inhibitors can be acquired through mutations in the FGFR gatekeeper residue, as clinically observed for FGFR4 in embryonal rhabdomyosarcoma and neuroendocrine breast carcinomas. Here we report on the use of a structure-based drug design to develop two selective, next-generation covalent FGFR inhibitors, the FGFR irreversible inhibitors 2 (FIIN-2) and 3 (FIIN-3). To our knowledge, FIIN-2 and FIIN-3 are the first inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. Because of the conformational flexibility of the reactive acrylamide substituent, FIIN-3 has the unprecedented ability to inhibit both the EGF receptor (EGFR) and FGFR covalently by targeting two distinct cysteine residues. We report the cocrystal structure of FGFR4 with FIIN-2, which unexpectedly exhibits a "DFG-out" covalent binding mode. The structural basis for dual FGFR and EGFR targeting by FIIN3 also is illustrated by crystal structures of FIIN-3 bound with FGFR4 V550L and EGFR L858R. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance and provide the first example, to our knowledge, of a kinase inhibitor that covalently targets cysteines located in different positions within the ATP-binding pocket.
-
-	Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors.,Tan L, Wang J, Tanizaki J, Huang Z, Aref AR, Rusan M, Zhu SJ, Zhang Y, Ercan D, Liao RG, Capelletti M, Zhou W, Hur W, Kim N, Sim T, Gaudet S, Barbie DA, Yeh JR, Yun CH, Hammerman PS, Mohammadi M, Janne PA, Gray NS Proc Natl Acad Sci U S A. 2014 Oct 27. pii: 201403438. PMID:25349422<ref>PMID:25349422</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 4r5s" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
	*[[Epidermal growth factor receptor 3D structures\|Epidermal growth factor receptor 3D structures]]		*[[Epidermal growth factor receptor 3D structures\|Epidermal growth factor receptor 3D structures]]
-	== References ==
-	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Receptor protein-tyrosine kinase]]~~	+	[[Category: Yun CH]]
-	[[Category: Yun~~, C H~~]]	+	[[Category: Zhu SJ]]
-	[[Category: Zhu~~, S J]]~~	+
-	~~[[Category: Egfr]]~~	+
-	~~[[Category: Fiin-3]]~~	+
-	~~[[Category: Kinase]]~~	+
-	~~[[Category: L858r]]~~	+
-	~~[[Category: Transferase~~]]	+

OCA at 05:08, 25 August 2022

OCA — Thu, 25 Aug 2022 05:08:07 GMT

←Older revision		Revision as of 05:08, 25 August 2022
Line 3:		Line 3:
	<StructureSection load='4r5s' size='340' side='right'caption='[[4r5s]], [[Resolution\|resolution]] 3.00Å' scene=''>		<StructureSection load='4r5s' size='340' side='right'caption='[[4r5s]], [[Resolution\|resolution]] 3.00Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4r5s]] 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=4R5S OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4R5S FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4r5s]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4R5S OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4R5S FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FI3:N-[4-({[(2,6-DICHLORO-3,5-DIMETHOXYPHENYL)CARBAMOYL](6-{[4-(4-METHYLPIPERAZIN-1-YL)PHENYL]AMINO}PYRIMIDIN-4-YL)AMINO}METHYL)PHENYL]PROPANAMIDE'>FI3</scene>~~</td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FI3:N-[4-({[(2,6-DICHLORO-3,5-DIMETHOXYPHENYL)CARBAMOYL](6-{[4-(4-METHYLPIPERAZIN-1-YL)PHENYL]AMINO}PYRIMIDIN-4-YL)AMINO}METHYL)PHENYL]PROPANAMIDE'>FI3</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'>[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='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'>[https://proteopedia.org/fgij/fg.htm?mol=4r5s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r5s OCA], [https://pdbe.org/4r5s PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4r5s RCSB], [https://www.ebi.ac.uk/pdbsum/4r5s PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4r5s ProSAT]</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=4r5s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r5s OCA], [~~http~~://pdbe.org/4r5s PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4r5s RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4r5s PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4r5s 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 ==
Line 24:		Line 23:

	==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: Large Structures]]		[[Category: Large Structures]]
	[[Category: Receptor protein-tyrosine kinase]]		[[Category: Receptor protein-tyrosine kinase]]

OCA at 10:37, 1 May 2019

OCA — Wed, 01 May 2019 10:37:35 GMT

←Older revision		Revision as of 10:37, 1 May 2019
Line 1:		Line 1:

	==Crystal structure of EGFR 696-1022 L858R in complex with FIIN-3==		==Crystal structure of EGFR 696-1022 L858R in complex with FIIN-3==
-	<StructureSection load='4r5s' size='340' side='right' caption='[[4r5s]], [[Resolution\|resolution]] 3.00Å' scene=''>	+	<StructureSection load='4r5s' size='340' side='right'caption='[[4r5s]], [[Resolution\|resolution]] 3.00Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4r5s]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4R5S OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4R5S FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4r5s]] 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=4R5S OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4R5S FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FI3:N-[4-({[(2,6-DICHLORO-3,5-DIMETHOXYPHENYL)CARBAMOYL](6-{[4-(4-METHYLPIPERAZIN-1-YL)PHENYL]AMINO}PYRIMIDIN-4-YL)AMINO}METHYL)PHENYL]PROPANAMIDE'>FI3</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FI3:N-[4-({[(2,6-DICHLORO-3,5-DIMETHOXYPHENYL)CARBAMOYL](6-{[4-(4-METHYLPIPERAZIN-1-YL)PHENYL]AMINO}PYRIMIDIN-4-YL)AMINO}METHYL)PHENYL]PROPANAMIDE'>FI3</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='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=4r5s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r5s OCA], [http://pdbe.org/4r5s PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4r5s RCSB], [http://www.ebi.ac.uk/pdbsum/4r5s PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4r5s ProSAT]</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=4r5s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r5s OCA], [http://pdbe.org/4r5s PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4r5s RCSB], [http://www.ebi.ac.uk/pdbsum/4r5s PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4r5s ProSAT]</span></td></tr>
Line 28:		Line 29:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Receptor protein-tyrosine kinase]]		[[Category: Receptor protein-tyrosine kinase]]
	[[Category: Yun, C H]]		[[Category: Yun, C H]]

OCA at 09:45, 11 August 2016

OCA — Thu, 11 Aug 2016 09:45:54 GMT

←Older revision		Revision as of 09:45, 11 August 2016
Line 1:		Line 1:
		+
	==Crystal structure of EGFR 696-1022 L858R in complex with FIIN-3==		==Crystal structure of EGFR 696-1022 L858R in complex with FIIN-3==
	<StructureSection load='4r5s' size='340' side='right' caption='[[4r5s]], [[Resolution\|resolution]] 3.00Å' scene=''>		<StructureSection load='4r5s' size='340' side='right' caption='[[4r5s]], [[Resolution\|resolution]] 3.00Å' scene=''>
Line 5:		Line 6:
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FI3:N-[4-({[(2,6-DICHLORO-3,5-DIMETHOXYPHENYL)CARBAMOYL](6-{[4-(4-METHYLPIPERAZIN-1-YL)PHENYL]AMINO}PYRIMIDIN-4-YL)AMINO}METHYL)PHENYL]PROPANAMIDE'>FI3</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FI3:N-[4-({[(2,6-DICHLORO-3,5-DIMETHOXYPHENYL)CARBAMOYL](6-{[4-(4-METHYLPIPERAZIN-1-YL)PHENYL]AMINO}PYRIMIDIN-4-YL)AMINO}METHYL)PHENYL]PROPANAMIDE'>FI3</scene></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=4r5s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r5s OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4r5s RCSB], [http://www.ebi.ac.uk/pdbsum/4r5s 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=4r5s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r5s OCA], [http://pdbe.org/4r5s PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4r5s RCSB], [http://www.ebi.ac.uk/pdbsum/4r5s PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4r5s ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 19:		Line 20:
	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 4r5s" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Epidermal Growth Factor Receptor\|Epidermal Growth Factor Receptor]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 06:58, 12 November 2014

OCA — Wed, 12 Nov 2014 06:58:29 GMT

←Older revision		Revision as of 06:58, 12 November 2014
Line 1:		Line 1:
-	'''~~Unreleased~~ structure'''	+	==Crystal structure of EGFR 696-1022 L858R in complex with FIIN-3==
		+	<StructureSection load='4r5s' size='340' side='right' caption='[[4r5s]], [[Resolution\|resolution]] 3.00Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[4r5s]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4R5S OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4R5S FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FI3:N-[4-({[(2,6-DICHLORO-3,5-DIMETHOXYPHENYL)CARBAMOYL](6-{[4-(4-METHYLPIPERAZIN-1-YL)PHENYL]AMINO}PYRIMIDIN-4-YL)AMINO}METHYL)PHENYL]PROPANAMIDE'>FI3</scene></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=4r5s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r5s OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4r5s RCSB], [http://www.ebi.ac.uk/pdbsum/4r5s 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.
		+	== 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 ==
		+	The human FGF receptors (FGFRs) play critical roles in various human cancers, and several FGFR inhibitors are currently under clinical investigation. Resistance usually results from selection for mutant kinases that are impervious to the action of the drug or from up-regulation of compensatory signaling pathways. Preclinical studies have demonstrated that resistance to FGFR inhibitors can be acquired through mutations in the FGFR gatekeeper residue, as clinically observed for FGFR4 in embryonal rhabdomyosarcoma and neuroendocrine breast carcinomas. Here we report on the use of a structure-based drug design to develop two selective, next-generation covalent FGFR inhibitors, the FGFR irreversible inhibitors 2 (FIIN-2) and 3 (FIIN-3). To our knowledge, FIIN-2 and FIIN-3 are the first inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. Because of the conformational flexibility of the reactive acrylamide substituent, FIIN-3 has the unprecedented ability to inhibit both the EGF receptor (EGFR) and FGFR covalently by targeting two distinct cysteine residues. We report the cocrystal structure of FGFR4 with FIIN-2, which unexpectedly exhibits a "DFG-out" covalent binding mode. The structural basis for dual FGFR and EGFR targeting by FIIN3 also is illustrated by crystal structures of FIIN-3 bound with FGFR4 V550L and EGFR L858R. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance and provide the first example, to our knowledge, of a kinase inhibitor that covalently targets cysteines located in different positions within the ATP-binding pocket.

-	~~The entry 4r5s is ON HOLD~~	+	Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors.,Tan L, Wang J, Tanizaki J, Huang Z, Aref AR, Rusan M, Zhu SJ, Zhang Y, Ercan D, Liao RG, Capelletti M, Zhou W, Hur W, Kim N, Sim T, Gaudet S, Barbie DA, Yeh JR, Yun CH, Hammerman PS, Mohammadi M, Janne PA, Gray NS Proc Natl Acad Sci U S A. 2014 Oct 27. pii: 201403438. PMID:25349422<ref>PMID:25349422</ref>

-	~~Authors: Zhu~~, S.J., Yun, C.H.	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-		+	</div>
-	~~Description~~: ~~Crystal structure of EGFR 696-1022 L858R in complex with FIIN~~-3	+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Receptor protein-tyrosine kinase]]
		+	[[Category: Yun, C H]]
		+	[[Category: Zhu, S J]]
		+	[[Category: Egfr]]
		+	[[Category: Fiin-3]]
		+	[[Category: Kinase]]
		+	[[Category: L858r]]
		+	[[Category: Transferase]]

OCA: Protected "4r5s" [edit=sysop:move=sysop]

OCA — Wed, 27 Aug 2014 07:03:08 GMT

Protected "4r5s" [edit=sysop:move=sysop]

←Older revision

Revision as of 07:03, 27 August 2014

OCA: New page: '''Unreleased structure''' The entry 4r5s is ON HOLD Authors: Zhu, S.J., Yun, C.H. Description: Crystal structure of EGFR 696-1022 L858R in complex with FIIN-3

OCA — Wed, 27 Aug 2014 07:03:07 GMT

New page: '''Unreleased structure''' The entry 4r5s is ON HOLD Authors: Zhu, S.J., Yun, C.H. Description: Crystal structure of EGFR 696-1022 L858R in complex with FIIN-3

New page

'''Unreleased structure'''

The entry 4r5s is ON HOLD

Authors: Zhu, S.J., Yun, C.H.

Description: Crystal structure of EGFR 696-1022 L858R in complex with FIIN-3