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| | <StructureSection load='5e80' size='340' side='right'caption='[[5e80]], [[Resolution|resolution]] 2.60Å' scene=''> | | <StructureSection load='5e80' size='340' side='right'caption='[[5e80]], [[Resolution|resolution]] 2.60Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5e80]] is a 2 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=5E80 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5E80 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5e80]] is a 2 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=5E80 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5E80 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5KP:N-(3-CHLORO-2-METHYLPHENYL)-4-(3,4-DIMETHYL-7-OXO-2-PHENYL-2,7-DIHYDRO-6H-PYRAZOLO[3,4-D]PYRIDAZIN-6-YL)BUTANAMIDE'>5KP</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]] 2.6Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PDE6D, PDED ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5KP:N-(3-CHLORO-2-METHYLPHENYL)-4-(3,4-DIMETHYL-7-OXO-2-PHENYL-2,7-DIHYDRO-6H-PYRAZOLO[3,4-D]PYRIDAZIN-6-YL)BUTANAMIDE'>5KP</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5e80 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5e80 OCA], [http://pdbe.org/5e80 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5e80 RCSB], [http://www.ebi.ac.uk/pdbsum/5e80 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5e80 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=5e80 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5e80 OCA], [https://pdbe.org/5e80 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5e80 RCSB], [https://www.ebi.ac.uk/pdbsum/5e80 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5e80 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PDE6D_HUMAN PDE6D_HUMAN]] Acts as a GTP specific dissociation inhibitor (GDI). Increases the affinity of ARL3 for GTP by several orders of magnitude and does so by decreasing the nucleotide dissociation rate. Stabilizes Arl3-GTP by decreasing the nucleotide dissociation (By similarity). | + | [https://www.uniprot.org/uniprot/PDE6D_HUMAN PDE6D_HUMAN] Acts as a GTP specific dissociation inhibitor (GDI). Increases the affinity of ARL3 for GTP by several orders of magnitude and does so by decreasing the nucleotide dissociation rate. Stabilizes Arl3-GTP by decreasing the nucleotide dissociation (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: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Fansa, E K]] | + | [[Category: Fansa EK]] |
| - | [[Category: Ismail, S]] | + | [[Category: Ismail S]] |
| - | [[Category: Murarka, S]] | + | [[Category: Murarka S]] |
| - | [[Category: Wittinghofer, A]] | + | [[Category: Wittinghofer A]] |
| - | [[Category: Gdi-like solubilizing factor]]
| + | |
| - | [[Category: Immunoglobulin-like beta-sandwich]]
| + | |
| - | [[Category: Lipid binding protein]]
| + | |
| - | [[Category: Prenyl binding protein /inhibitor]]
| + | |
| Structural highlights
Function
PDE6D_HUMAN Acts as a GTP specific dissociation inhibitor (GDI). Increases the affinity of ARL3 for GTP by several orders of magnitude and does so by decreasing the nucleotide dissociation rate. Stabilizes Arl3-GTP by decreasing the nucleotide dissociation (By similarity).
Publication Abstract from PubMed
The prenyl-binding protein PDEdelta is crucial for the plasma membrane localization of prenylated Ras. Recently, we have reported that the small-molecule Deltarasin binds to the prenyl-binding pocket of PDEdelta, and impairs Ras enrichment at the plasma membrane, thereby affecting the proliferation of KRas-dependent human pancreatic ductal adenocarcinoma cell lines. Here, using structure-based compound design, we have now identified pyrazolopyridazinones as a novel, unrelated chemotype that binds to the prenyl-binding pocket of PDEdelta with high affinity, thereby displacing prenylated Ras proteins in cells. Our results show that the new PDEdelta inhibitor, named Deltazinone 1, is highly selective, exhibits less unspecific cytotoxicity than the previously reported Deltarasin and demonstrates a high correlation with the phenotypic effect of PDEdelta knockdown in a set of human pancreatic cancer cell lines.
Identification of pyrazolopyridazinones as PDEdelta inhibitors.,Papke B, Murarka S, Vogel HA, Martin-Gago P, Kovacevic M, Truxius DC, Fansa EK, Ismail S, Zimmermann G, Heinelt K, Schultz-Fademrecht C, Al Saabi A, Baumann M, Nussbaumer P, Wittinghofer A, Waldmann H, Bastiaens PI Nat Commun. 2016 Apr 20;7:11360. doi: 10.1038/ncomms11360. PMID:27094677[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Papke B, Murarka S, Vogel HA, Martin-Gago P, Kovacevic M, Truxius DC, Fansa EK, Ismail S, Zimmermann G, Heinelt K, Schultz-Fademrecht C, Al Saabi A, Baumann M, Nussbaumer P, Wittinghofer A, Waldmann H, Bastiaens PI. Identification of pyrazolopyridazinones as PDEdelta inhibitors. Nat Commun. 2016 Apr 20;7:11360. doi: 10.1038/ncomms11360. PMID:27094677 doi:http://dx.doi.org/10.1038/ncomms11360
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