5ml4: Difference between revisions
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==The crystal structure of PDE6D in complex to inhibitor-7== | ==The crystal structure of PDE6D in complex to inhibitor-7== | ||
<StructureSection load='5ml4' size='340' side='right' caption='[[5ml4]], [[Resolution|resolution]] 2.40Å' scene=''> | <StructureSection load='5ml4' size='340' side='right'caption='[[5ml4]], [[Resolution|resolution]] 2.40Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5ml4]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ML4 OCA]. For a <b>guided tour on the structure components</b> use [http:// | <table><tr><td colspan='2'>[[5ml4]] 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=5ML4 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5ML4 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=RRQ:4-[[[4-[(4-CHLOROPHENYL)METHYL-CYCLOPENTYL-SULFAMOYL]PHENYL]SULFONYL-(PIPERIDIN-4-YLMETHYL)AMINO]METHYL]-2-(METHYLAMINO)BENZOIC+ACID'>RRQ</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=RRQ:4-[[[4-[(4-CHLOROPHENYL)METHYL-CYCLOPENTYL-SULFAMOYL]PHENYL]SULFONYL-(PIPERIDIN-4-YLMETHYL)AMINO]METHYL]-2-(METHYLAMINO)BENZOIC+ACID'>RRQ</scene></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http:// | <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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5ml4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ml4 OCA], [http://pdbe.org/5ml4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ml4 RCSB], [http://www.ebi.ac.uk/pdbsum/5ml4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ml4 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | == Function == | ||
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</div> | </div> | ||
<div class="pdbe-citations 5ml4" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 5ml4" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | |||
[[Category: Fansa, E K]] | [[Category: Fansa, E K]] | ||
[[Category: Martin-Gago, P]] | [[Category: Martin-Gago, P]] | ||
Revision as of 10:22, 19 August 2020
The crystal structure of PDE6D in complex to inhibitor-7The crystal structure of PDE6D in complex to inhibitor-7
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 PubMedSmall-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 AlsoReferences
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