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4g31

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Revision as of 20:22, 19 October 2022

Crystal Structure of GSK6414 Bound to PERK (R587-R1092, delete A660-T867) at 2.28 A Resolution

Structural highlights

4g31 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

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.

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^[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
↑ 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. 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). J Med Chem. 2012 Jul 24. PMID:22827572 doi:10.1021/jm300713s

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4g31"

Categories: Homo sapiens | Large Structures | Axten JM | Gampe RT

@@ Line 1: / Line 1: @@
 ==Crystal Structure of GSK6414 Bound to PERK (R587-R1092, delete A660-T867) at 2.28 A Resolution==
-<StructureSection load='4g31' size='340' side='right' caption='[[4g31]], [[Resolution|resolution]] 2.28&Aring;' scene=''>
+<StructureSection load='4g31' size='340' side='right'caption='[[4g31]], [[Resolution|resolution]] 2.28&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4g31]] 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=4G31 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4G31 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4g31]] 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=4G31 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4G31 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0WH:1-[5-(4-AMINO-7-METHYL-7H-PYRROLO[2,3-D]PYRIMIDIN-5-YL)-2,3-DIHYDRO-1H-INDOL-1-YL]-2-[3-(TRIFLUOROMETHYL)PHENYL]ETHANONE'>0WH</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0WH:1-[5-(4-AMINO-7-METHYL-7H-PYRROLO[2,3-D]PYRIMIDIN-5-YL)-2,3-DIHYDRO-1H-INDOL-1-YL]-2-[3-(TRIFLUOROMETHYL)PHENYL]ETHANONE'>0WH</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3qd2|3qd2]], [[4g34|4g34]]</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=4g31 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4g31 OCA], [https://pdbe.org/4g31 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4g31 RCSB], [https://www.ebi.ac.uk/pdbsum/4g31 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4g31 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=4g31 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4g31 OCA], [http://pdbe.org/4g31 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4g31 RCSB], [http://www.ebi.ac.uk/pdbsum/4g31 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4g31 ProSAT]</span></td></tr>
 </table>
 == 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 ==
-[[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 ==
@@ Line 27: / Line 24: @@
 __TOC__
 </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]]
-[[Category: Deletion mutant]]
-[[Category: Synthetic inhibitor]]
-[[Category: Transferase-transferase inhibitor complex]]

4g31

From Proteopedia

Revision as of 20:22, 19 October 2022

Crystal Structure of GSK6414 Bound to PERK (R587-R1092, delete A660-T867) at 2.28 A Resolution

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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