5u8l - Revision history

OCA at 12:29, 23 September 2020

OCA — Wed, 23 Sep 2020 12:29:32 GMT

←Older revision		Revision as of 12:29, 23 September 2020
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	==Crystal structure of EGFR kinase domain in complex with a sulfonyl fluoride probe XO44==		==Crystal structure of EGFR kinase domain in complex with a sulfonyl fluoride probe XO44==
-	<StructureSection load='5u8l' size='340' side='right' caption='[[5u8l]], [[Resolution\|resolution]] 1.60Å' scene=''>	+	<StructureSection load='5u8l' size='340' side='right'caption='[[5u8l]], [[Resolution\|resolution]] 1.60Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5u8l]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5U8L OCA]. For a <b>guided tour on the structure components</b> use [http://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5U8L FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5u8l]] 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=5U8L OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5U8L FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=O44:4-[(4-{4-[(3-CYCLOPROPYL-1H-PYRAZOL-5-YL)AMINO]-6-[(PROP-2-YN-1-YL)CARBAMOYL]PYRIMIDIN-2-YL}PIPERAZIN-1-YL)METHYL]BENZENE-1-SULFONYL+FLUORIDE'>O44</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=O44:4-[(4-{4-[(3-CYCLOPROPYL-1H-PYRAZOL-5-YL)AMINO]-6-[(PROP-2-YN-1-YL)CARBAMOYL]PYRIMIDIN-2-YL}PIPERAZIN-1-YL)METHYL]BENZENE-1-SULFONYL+FLUORIDE'>O44</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=5u8l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5u8l OCA], [http://pdbe.org/5u8l PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5u8l RCSB], [http://www.ebi.ac.uk/pdbsum/5u8l PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5u8l ProSAT]</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=5u8l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5u8l OCA], [http://pdbe.org/5u8l PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5u8l RCSB], [http://www.ebi.ac.uk/pdbsum/5u8l PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5u8l ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 21:		Line 22:
	</div>		</div>
	<div class="pdbe-citations 5u8l" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 5u8l" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[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: Receptor protein-tyrosine kinase]]		[[Category: Receptor protein-tyrosine kinase]]
	[[Category: Ferre, R]]		[[Category: Ferre, R]]

OCA at 23:31, 25 January 2017

OCA — Wed, 25 Jan 2017 23:31:17 GMT

←Older revision		Revision as of 23:31, 25 January 2017
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-	'''Unreleased structure'''

-	~~The entry~~ 5u8l is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Crystal structure of EGFR kinase domain in complex with a sulfonyl fluoride probe XO44==
		+	<StructureSection load='5u8l' size='340' side='right' caption='[[5u8l]], [[Resolution\|resolution]] 1.60Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5u8l]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5U8L OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5U8L FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=O44:4-[(4-{4-[(3-CYCLOPROPYL-1H-PYRAZOL-5-YL)AMINO]-6-[(PROP-2-YN-1-YL)CARBAMOYL]PYRIMIDIN-2-YL}PIPERAZIN-1-YL)METHYL]BENZENE-1-SULFONYL+FLUORIDE'>O44</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'>[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=5u8l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5u8l OCA], [http://pdbe.org/5u8l PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5u8l RCSB], [http://www.ebi.ac.uk/pdbsum/5u8l PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5u8l ProSAT]</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 ==
		+	Protein kinases comprise a large family of structurally related enzymes. A major goal in kinase-inhibitor development is to selectively engage the desired kinase while avoiding myriad off-target kinases. However, quantifying inhibitor interactions with multiple endogenous kinases in live cells remains an unmet challenge. Here, we report the design of sulfonyl fluoride probes that covalently label a broad swath of the intracellular kinome with high efficiency. Protein crystallography and mass spectrometry confirmed a chemoselective reaction between the sulfonyl fluoride and a conserved lysine in the ATP binding site. Optimized probe 2 (XO44) covalently modified up to 133 endogenous kinases, efficiently competing with high intracellular concentrations of ATP. We employed probe 2 and label-free mass spectrometry to quantify intracellular kinase engagement by the approved drug, dasatinib. The data revealed saturable dasatinib binding to a small subset of kinase targets at clinically relevant concentrations, highlighting the utility of lysine-targeted sulfonyl fluoride probes in demanding chemoproteomic applications.

-	~~Authors:~~ Gajiwala, K.S., ~~Ferre, R~~.	+	Broad-Spectrum Kinase Profiling in Live Cells with Lysine-Targeted Sulfonyl Fluoride Probes.,Zhao Q, Ouyang X, Wan X, Gajiwala KS, Kath JC, Jones LH, Burlingame AL, Taunton J J Am Chem Soc. 2017 Jan 18;139(2):680-685. doi: 10.1021/jacs.6b08536. Epub 2017, Jan 4. PMID:28051857<ref>PMID:28051857</ref>

-	~~Description: Crystal structure of EGFR kinase domain in complex with~~ a ~~sulfonyl fluoride probe XO44~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
		+	<div class="pdbe-citations 5u8l" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Receptor protein-tyrosine kinase]]
	[[Category: Ferre, R]]		[[Category: Ferre, R]]
-	[[Category: Gajiwala, K.S]]	+	[[Category: Gajiwala, K S]]
		+	[[Category: Kinase covalent probe covalent inhibitor complex]]
		+	[[Category: Transferase-transferase inhibitor complex]]

OCA at 14:30, 18 January 2017

OCA — Wed, 18 Jan 2017 14:30:40 GMT

←Older revision		Revision as of 14:30, 18 January 2017
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 5u8l is ON HOLD	+	The entry 5u8l is ON HOLD until Paper Publication

	Authors: Gajiwala, K.S., Ferre, R.		Authors: Gajiwala, K.S., Ferre, R.

OCA: Protected "5u8l" [edit=sysop:move=sysop]

OCA — Thu, 22 Dec 2016 20:32:49 GMT

Protected "5u8l" [edit=sysop:move=sysop]

←Older revision

Revision as of 20:32, 22 December 2016

OCA: New page: '''Unreleased structure''' The entry 5u8l is ON HOLD Authors: Gajiwala, K.S., Ferre, R. Description: Crystal structure of EGFR kinase domain in complex with a sulfonyl fluoride probe X...

OCA — Thu, 22 Dec 2016 20:32:48 GMT

New page: '''Unreleased structure''' The entry 5u8l is ON HOLD Authors: Gajiwala, K.S., Ferre, R. Description: Crystal structure of EGFR kinase domain in complex with a sulfonyl fluoride probe X...

New page

'''Unreleased structure'''

The entry 5u8l is ON HOLD

Authors: Gajiwala, K.S., Ferre, R.

Description: Crystal structure of EGFR kinase domain in complex with a sulfonyl fluoride probe XO44
[[Category: Unreleased Structures]]
[[Category: Ferre, R]]
[[Category: Gajiwala, K.S]]