8aoe: Difference between revisions
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[8aoe]] is a 1 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=8AOE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8AOE FirstGlance]. <br> | <table><tr><td colspan='2'>[[8aoe]] is a 1 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=8AOE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8AOE FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=N6U:~{N}-(1~{H}-pyrrolo[2,3-b]pyridin-4-yl)ethanesulfonamide'>N6U</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.687Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=N6U:~{N}-(1~{H}-pyrrolo[2,3-b]pyridin-4-yl)ethanesulfonamide'>N6U</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=8aoe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8aoe OCA], [https://pdbe.org/8aoe PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8aoe RCSB], [https://www.ebi.ac.uk/pdbsum/8aoe PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8aoe ProSAT]</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=8aoe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8aoe OCA], [https://pdbe.org/8aoe PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8aoe RCSB], [https://www.ebi.ac.uk/pdbsum/8aoe PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8aoe ProSAT]</span></td></tr> | ||
</table> | </table> | ||
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<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
Fragment-based drug discovery (FBDD) has become an established method for the identification of efficient starting points for drug discovery programs. In recent years, electrophilic fragment screening has garnered increased attention from both academia and industry to identify novel covalent hits for tool compound or drug development against challenging drug targets. Herein, we describe the design and characterization of an acrylamide-focused electrophilic fragment library and screening campaign against extracellular signal-regulated kinase 2 (ERK2) using high-throughput protein crystallography as the primary hit-finding technology. Several fragments were found to have covalently modified the adenosine triphosphate (ATP) binding pocket Cys166 residue. From these hits, 22, a covalent ATP-competitive inhibitor with improved potency (ERK2 | Fragment-based drug discovery (FBDD) has become an established method for the identification of efficient starting points for drug discovery programs. In recent years, electrophilic fragment screening has garnered increased attention from both academia and industry to identify novel covalent hits for tool compound or drug development against challenging drug targets. Herein, we describe the design and characterization of an acrylamide-focused electrophilic fragment library and screening campaign against extracellular signal-regulated kinase 2 (ERK2) using high-throughput protein crystallography as the primary hit-finding technology. Several fragments were found to have covalently modified the adenosine triphosphate (ATP) binding pocket Cys166 residue. From these hits, 22, a covalent ATP-competitive inhibitor with improved potency (ERK2 IC(50) = 7.8 muM), was developed. | ||
X-ray Screening of an Electrophilic Fragment Library and Application toward the Development of a Novel ERK 1/2 Covalent Inhibitor.,St Denis JD, Chessari G, Cleasby A, Cons BD, Cowan S, Dalton SE, East C, Murray CW, O'Reilly M, Peakman T, Rapti M, Stow JL J Med Chem. 2022 Sep 22;65(18):12319-12333. doi: 10.1021/acs.jmedchem.2c01044., Epub 2022 Sep 13. PMID:36101934<ref>PMID:36101934</ref> | X-ray Screening of an Electrophilic Fragment Library and Application toward the Development of a Novel ERK 1/2 Covalent Inhibitor.,St Denis JD, Chessari G, Cleasby A, Cons BD, Cowan S, Dalton SE, East C, Murray CW, O'Reilly M, Peakman T, Rapti M, Stow JL J Med Chem. 2022 Sep 22;65(18):12319-12333. doi: 10.1021/acs.jmedchem.2c01044. , Epub 2022 Sep 13. PMID:36101934<ref>PMID:36101934</ref> | ||
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 8aoe" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 8aoe" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Mitogen-activated protein kinase 3D structures|Mitogen-activated protein kinase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||