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| | <StructureSection load='5ml3' size='340' side='right'caption='[[5ml3]], [[Resolution|resolution]] 1.40Å' scene=''> | | <StructureSection load='5ml3' size='340' side='right'caption='[[5ml3]], [[Resolution|resolution]] 1.40Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5ml3]] 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=5ML3 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5ML3 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5ml3]] 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=5ML3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5ML3 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DL3:~{N}1-[(4-CHLOROPHENYL)METHYL]-~{N}1-CYCLOPENTYL-~{N}4-[[2-(METHYLAMINO)PYRIMIDIN-4-YL]METHYL]-~{N}4-(PIPERIDIN-4-YLMETHYL)BENZENE-1,4-DISULFONAMIDE'>DL3</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]] 1.4Å</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=DL3:~{N}1-[(4-CHLOROPHENYL)METHYL]-~{N}1-CYCLOPENTYL-~{N}4-[[2-(METHYLAMINO)PYRIMIDIN-4-YL]METHYL]-~{N}4-(PIPERIDIN-4-YLMETHYL)BENZENE-1,4-DISULFONAMIDE'>DL3</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=5ml3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ml3 OCA], [http://pdbe.org/5ml3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ml3 RCSB], [http://www.ebi.ac.uk/pdbsum/5ml3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ml3 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=5ml3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ml3 OCA], [https://pdbe.org/5ml3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ml3 RCSB], [https://www.ebi.ac.uk/pdbsum/5ml3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ml3 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: Martin-Gago, P]] | + | [[Category: Martin-Gago P]] |
| - | [[Category: Waldmann, H]] | + | [[Category: Waldmann H]] |
| - | [[Category: Wittinghofer, A]] | + | [[Category: Wittinghofer A]] |
| - | [[Category: Arl2]]
| + | |
| - | [[Category: Farnesylated kra]]
| + | |
| - | [[Category: Lipid binding protein]]
| + | |
| - | [[Category: Plasma membrane]]
| + | |
| - | [[Category: Prenyl binding protein]]
| + | |
| 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
Small-molecule inhibition of the interaction between the KRas oncoprotein and the chaperone PDE6delta impairs KRas spatial organization and signaling in cells. However, despite potent binding in vitro (KD <10 nm), interference with Ras signaling and growth inhibition require 5-20 mum compound concentrations. We demonstrate that these findings can be explained by fast release of high-affinity inhibitors from PDE6delta by the release factor Arl2. This limitation is overcome by novel highly selective inhibitors that bind to PDE6delta with up to 7 hydrogen bonds, resulting in picomolar affinity. Their release by Arl2 is greatly decreased, and representative compounds selectively inhibit growth of KRas mutated and -dependent cells with the highest activity recorded yet. Our findings indicate that very potent inhibitors of the KRas-PDE6delta interaction may impair the growth of tumors driven by oncogenic KRas.
A PDE6delta-KRas Inhibitor Chemotype with up to Seven H-Bonds and Picomolar Affinity that Prevents Efficient Inhibitor Release by Arl2.,Martin-Gago P, Fansa EK, Klein CH, Murarka S, Janning P, Schurmann M, Metz M, Ismail S, Schultz-Fademrecht C, Baumann M, Bastiaens PI, Wittinghofer A, Waldmann H Angew Chem Int Ed Engl. 2017 Jan 20. doi: 10.1002/anie.201610957. PMID:28106325[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Martin-Gago P, Fansa EK, Klein CH, Murarka S, Janning P, Schurmann M, Metz M, Ismail S, Schultz-Fademrecht C, Baumann M, Bastiaens PI, Wittinghofer A, Waldmann H. A PDE6delta-KRas Inhibitor Chemotype with up to Seven H-Bonds and Picomolar Affinity that Prevents Efficient Inhibitor Release by Arl2. Angew Chem Int Ed Engl. 2017 Jan 20. doi: 10.1002/anie.201610957. PMID:28106325 doi:http://dx.doi.org/10.1002/anie.201610957
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