5hcy: Difference between revisions

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-'''Unreleased structure'''
-The entry 5hcy is ON HOLD  until Paper Publication
+==EGFR kinase domain mutant "TMLR" with 3-carboxamide azaindole compound 13==
+<StructureSection load='5hcy' size='340' side='right' caption='[[5hcy]], [[Resolution|resolution]] 2.46&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5hcy]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HCY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5HCY FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=60D:6-[[2-(1-CYCLOPROPYLSULFONYLPYRAZOL-4-YL)PYRIMIDIN-4-YL]AMINO]-~{N}-(OXAN-4-YL)-1-PROPAN-2-YL-PYRROLO[3,2-C]PYRIDINE-3-CARBOXAMIDE'>60D</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5hcx|5hcx]], [[5hcz|5hcz]]</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=5hcy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hcy OCA], [http://pdbe.org/5hcy PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5hcy RCSB], [http://www.ebi.ac.uk/pdbsum/5hcy PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5hcy 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 ==
+Inhibitors targeting the activating mutants of the epidermal growth factor receptor (EGFR) have found success in the treatment of EGFR-mutant positive non-small cell lung cancer. A secondary point mutation (T790M) in the inhibitor binding site has been linked to the acquired resistance against those first generation therapeutics. Herein, we describe the lead optimization of a series of reversible, pan-mutant (L858R, del746-750, T790M/L858R and T790M/del746-750) EGFR inhibitors. Using a non-covalent double mutant (T790M/L858R and T790M/del746-750) selective EGFR inhibitor (2) as a starting point, activities against the single mutants (L858R and del746-750) were introduced through a series of structure-guided modifications. The in vitro ADME-PK properties of the lead molecules were further optimized through a number of rational structural changes. The resulting inhibitor (21) exhibited excellent cellular activity against both the single and double mutants of EGFR, demonstrated target engagement in vivo and ADME-PK properties that are suitable for further evaluation. The reversible, non-covalent inhibitors described complement the covalent pan-mutant EGFR inhibitors that have shown encouraging results in recent clinical trials.
-Authors: Eigenbrot, C., Yu, C.
+Discovery of a Non-Covalent, Mutant-Selective Epidermal Growth Factor Receptor Inhibitor.,Chan BK, Hanan EJ, Bowman K, Bryan MC, Burdick DJ, Chan EW, Chen Y, Clausen S, Dela Vega T, Dotson J, Eigenbrot C, Elliott RL, Heald RA, Jackson PS, Knight JD, La H, Lainchbury MD, Malek S, Purkey HE, Schaefer G, Schmidt S, Seward EM, Sideris S, Shao L, Wang S, Yeap KS, Yen I, Yu C, Heffron TP J Med Chem. 2016 Aug 26. PMID:27564586<ref>PMID:27564586</ref>
-Description: EGFR kinase domain mutant ""TMLR"" with 3-carboxamide azaindole compound 13
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 5hcy" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Receptor protein-tyrosine kinase]]
 [[Category: Eigenbrot, C]]
 [[Category: Yu, C]]
+[[Category: Inhibitor]]
+[[Category: Protein kinase]]
+[[Category: Transferase-transferase inhibitor complex]]