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| | ==Crystal Structure of GSK6924 Bound to PERK (R587-R1092, delete A660-T867) at 2.70 A Resolution== | | ==Crystal Structure of GSK6924 Bound to PERK (R587-R1092, delete A660-T867) at 2.70 A Resolution== |
| - | <StructureSection load='4g34' size='340' side='right' caption='[[4g34]], [[Resolution|resolution]] 2.70Å' scene=''> | + | <StructureSection load='4g34' size='340' side='right'caption='[[4g34]], [[Resolution|resolution]] 2.70Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4g34]] 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=4G34 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4G34 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4g34]] 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=4G34 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4G34 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=924:1-[5-(4-AMINOTHIENO[3,2-C]PYRIDIN-3-YL)-2,3-DIHYDRO-1H-INDOL-1-YL]-2-PHENYLETHANONE'>924</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]] 2.7Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3qd2|3qd2]], [[4g31|4g31]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=924:1-[5-(4-AMINOTHIENO[3,2-C]PYRIDIN-3-YL)-2,3-DIHYDRO-1H-INDOL-1-YL]-2-PHENYLETHANONE'>924</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">EIF2AK3, PEK, PERK ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4g34 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4g34 OCA], [https://pdbe.org/4g34 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4g34 RCSB], [https://www.ebi.ac.uk/pdbsum/4g34 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4g34 ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr>
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| - | <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=4g34 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4g34 OCA], [http://pdbe.org/4g34 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4g34 RCSB], [http://www.ebi.ac.uk/pdbsum/4g34 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4g34 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/E2AK3_HUMAN E2AK3_HUMAN]] Wolcott-Rallison syndrome. The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:10932183</ref> | + | [https://www.uniprot.org/uniprot/E2AK3_HUMAN E2AK3_HUMAN] Wolcott-Rallison syndrome. The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:10932183</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/E2AK3_HUMAN E2AK3_HUMAN]] Phosphorylates the alpha subunit of eukaryotic translation-initiation factor 2 (EIF2), leading to its inactivation and thus to a rapid reduction of translational initiation and repression of global protein synthesis. Serves as a critical effector of unfolded protein response (UPR)-induced G1 growth arrest due to the loss of cyclin-D1 (CCND1) (By similarity). | + | [https://www.uniprot.org/uniprot/E2AK3_HUMAN E2AK3_HUMAN] Phosphorylates the alpha subunit of eukaryotic translation-initiation factor 2 (EIF2), leading to its inactivation and thus to a rapid reduction of translational initiation and repression of global protein synthesis. Serves as a critical effector of unfolded protein response (UPR)-induced G1 growth arrest due to the loss of cyclin-D1 (CCND1) (By similarity). |
| - | <div style="background-color:#fffaf0;">
| + | |
| - | == Publication Abstract from PubMed ==
| + | |
| - | PKR-like Endoplasmic Reticulum Kinase (PERK) is activated in response to a variety of endoplasmic reticulum stresses implicated in numerous disease states. Evidence that PERK is implicated in tumorigenesis and cancer cell survival stimulated our search for small molecule inhibitors. Through screening and lead optimization using the human PERK crystal structure, we discovered compound 38 (GSK2606414), an orally available, potent and selective PERK inhibitor. Compound 38 inhibits PERK activation in cells and inhibits the growth of a human tumor xenograft in mice.
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| - | | + | |
| - | Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-p yrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a Potent and Selective First-in-Class Inhibitor of PKR-like Endoplasmic Reticulum Kinase (PERK).,Axten JM, Medina JR, Feng Y, Shu A, Romeril S, Grant S, Li WH, Heerding DA, Minthorn E, Mencken T, Atkins C, Liu Q, Rabindran S, Kumat R, Hong X, Goetz A, Stanley TB, Taylor D, Sigethy S, Tomberlin GH, Hassell A, Shewchuk LM, Gampe R J Med Chem. 2012 Jul 24. PMID:22827572<ref>PMID:22827572</ref>
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| - | </div>
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| - | <div class="pdbe-citations 4g34" style="background-color:#fffaf0;"></div>
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| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Non-specific serine/threonine protein kinase]] | + | [[Category: Large Structures]] |
| - | [[Category: Axten, J M]] | + | [[Category: Axten JM]] |
| - | [[Category: Gampe, R T]] | + | [[Category: Gampe RT]] |
| - | [[Category: Catalytic domain]]
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| - | [[Category: Deletion mutant]]
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| - | [[Category: Synthetic inhibitor]]
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| - | [[Category: Transferase-transferase inhibitor complex]]
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