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| | ==Co-crystal Structure of PERK bound to N-{5-[(6,7-dimethoxyquinolin-4-yl)oxy]pyridin-2-yl}-1-methyl-3-oxo-2-phenyl-5-(pyridin-4-yl)-2,3-dihydro-1H-pyrazole-4-carboxamide inhibitor== | | ==Co-crystal Structure of PERK bound to N-{5-[(6,7-dimethoxyquinolin-4-yl)oxy]pyridin-2-yl}-1-methyl-3-oxo-2-phenyl-5-(pyridin-4-yl)-2,3-dihydro-1H-pyrazole-4-carboxamide inhibitor== |
| - | <StructureSection load='4x7h' size='340' side='right' caption='[[4x7h]], [[Resolution|resolution]] 2.00Å' scene=''> | + | <StructureSection load='4x7h' size='340' side='right'caption='[[4x7h]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4x7h]] 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=4X7H OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4X7H FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4x7h]] 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=4X7H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4X7H FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3Z2:N-{5-[(6,7-DIMETHOXYQUINOLIN-4-YL)OXY]PYRIDIN-2-YL}-1-METHYL-3-OXO-2-PHENYL-5-(PYRIDIN-4-YL)-2,3-DIHYDRO-1H-PYRAZOLE-4-CARBOXAMIDE'>3Z2</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=3Z2:N-{5-[(6,7-DIMETHOXYQUINOLIN-4-YL)OXY]PYRIDIN-2-YL}-1-METHYL-3-OXO-2-PHENYL-5-(PYRIDIN-4-YL)-2,3-DIHYDRO-1H-PYRAZOLE-4-CARBOXAMIDE'>3Z2</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">[[4x7j|4x7j]], [[4x7k|4x7k]], [[4x7l|4x7l]], [[4x7n|4x7n]], [[4x7o|4x7o]]</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=4x7h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4x7h OCA], [https://pdbe.org/4x7h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4x7h RCSB], [https://www.ebi.ac.uk/pdbsum/4x7h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4x7h ProSAT]</span></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='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>
| + | |
| - | <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=4x7h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4x7h OCA], [http://pdbe.org/4x7h PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4x7h RCSB], [http://www.ebi.ac.uk/pdbsum/4x7h PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4x7h 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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Non-specific serine/threonine protein kinase]] | + | [[Category: Large Structures]] |
| - | [[Category: Bellon, S F]] | + | [[Category: Bellon SF]] |
| - | [[Category: Chen, H]] | + | [[Category: Chen H]] |
| - | [[Category: Long, A M]] | + | [[Category: Long AM]] |
| - | [[Category: Shaffer, P L]] | + | [[Category: Shaffer PL]] |
| - | [[Category: Catalytic domain]]
| + | |
| - | [[Category: Complex]]
| + | |
| - | [[Category: Transferase-transferase inhibitor]]
| + | |
| - | [[Category: Transferase-transferase inhibitor complex]]
| + | |
| Structural highlights
Disease
E2AK3_HUMAN Wolcott-Rallison syndrome. The disease is caused by mutations affecting the gene represented in this entry.[1]
Function
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).
Publication Abstract from PubMed
The structure-based design and optimization of a novel series of selective PERK inhibitors are described resulting in the identification of 44 as a potent, highly selective, and orally active tool compound suitable for PERK pathway biology exploration both in vitro and in vivo.
Discovery of 1H-Pyrazol-3(2H)-ones as Potent and Selective Inhibitors of Protein Kinase R-like Endoplasmic Reticulum Kinase (PERK).,Smith AL, Andrews KL, Beckmann H, Bellon SF, Beltran PJ, Booker S, Chen H, Chung YA, D'Angelo ND, Dao J, Dellamaggiore KR, Jaeckel P, Kendall R, Labitzke K, Long AM, Materna-Reichelt S, Mitchell P, Norman MH, Powers D, Rose M, Shaffer PL, Wu MM, Lipford JR J Med Chem. 2015 Jan 14. PMID:25587754[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Delepine M, Nicolino M, Barrett T, Golamaully M, Lathrop GM, Julier C. EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome. Nat Genet. 2000 Aug;25(4):406-9. PMID:10932183 doi:http://dx.doi.org/10.1038/78085
- ↑ Smith AL, Andrews KL, Beckmann H, Bellon SF, Beltran PJ, Booker S, Chen H, Chung YA, D'Angelo ND, Dao J, Dellamaggiore KR, Jaeckel P, Kendall R, Labitzke K, Long AM, Materna-Reichelt S, Mitchell P, Norman MH, Powers D, Rose M, Shaffer PL, Wu MM, Lipford JR. Discovery of 1H-Pyrazol-3(2H)-ones as Potent and Selective Inhibitors of Protein Kinase R-like Endoplasmic Reticulum Kinase (PERK). J Med Chem. 2015 Jan 14. PMID:25587754 doi:http://dx.doi.org/10.1021/jm5017494
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