6v66: Difference between revisions

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'''Unreleased structure'''


The entry 6v66 is ON HOLD  until Paper Publication
==EGFR(T790M/V948R) in complex with LN2899==
<StructureSection load='6v66' size='340' side='right'caption='[[6v66]], [[Resolution|resolution]] 1.79&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6V66 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6V66 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.79&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=QP1:N-{3-[(4-{4-(4-fluorophenyl)-2-[(2-methoxyethyl)sulfanyl]-1H-imidazol-5-yl}pyridin-2-yl)amino]-4-methoxyphenyl}propanamide'>QP1</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=6v66 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6v66 OCA], [https://pdbe.org/6v66 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6v66 RCSB], [https://www.ebi.ac.uk/pdbsum/6v66 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6v66 ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Acquired drug resistance in epidermal growth factor receptor (EGFR) mutant non-small-cell lung cancer is a persistent challenge in cancer therapy. Previous studies of trisubstituted imidazole inhibitors led to the serendipitous discovery of inhibitors that target the drug resistant EGFR(L858R/T790M/C797S) mutant with nanomolar potencies in a reversible binding mechanism. To dissect the molecular basis for their activity, we determined the binding modes of several trisubstituted imidazole inhibitors in complex with the EGFR kinase domain with X-ray crystallography. These structures reveal that the imidazole core acts as an H-bond acceptor for the catalytic lysine (K745) in the "alphaC-helix out" inactive state. Selective N-methylation of the H-bond accepting nitrogen ablates inhibitor potency, confirming the role of the K745 H-bond in potent, noncovalent inhibition of the C797S variant. Insights from these studies offer new strategies for developing next generation inhibitors targeting EGFR in non-small-cell lung cancer.


Authors:  
Structural Basis for EGFR Mutant Inhibition by Trisubstituted Imidazole Inhibitors.,Heppner DE, Gunther M, Wittlinger F, Laufer SA, Eck MJ J Med Chem. 2020 Apr 14. doi: 10.1021/acs.jmedchem.0c00200. PMID:32243152<ref>PMID:32243152</ref>


Description:  
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
<div class="pdbe-citations 6v66" style="background-color:#fffaf0;"></div>
 
==See Also==
*[[Epidermal growth factor receptor 3D structures|Epidermal growth factor receptor 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Eck MJ]]
[[Category: Heppner DE]]
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