5ml4: Difference between revisions
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The | ==The crystal structure of PDE6D in complex to inhibitor-7== | ||
<StructureSection load='5ml4' size='340' side='right' caption='[[5ml4]], [[Resolution|resolution]] 2.40Å' scene=''> | |||
== 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://oca.weizmann.ac.il/oca-docs/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> | |||
<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=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> | |||
== 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). | |||
<div style="background-color:#fffaf0;"> | |||
== 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<ref>PMID:28106325</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
[[Category: | <div class="pdbe-citations 5ml4" style="background-color:#fffaf0;"></div> | ||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Fansa, E K]] | |||
[[Category: Martin-Gago, P]] | [[Category: Martin-Gago, P]] | ||
[[Category: Wittinghofer, A]] | [[Category: Wittinghofer, A]] | ||
[[Category: | [[Category: Waldmann, H]] | ||
[[Category: Arl2]] | |||
[[Category: Farnesylated kra]] | |||
[[Category: Lipid binding protein]] | |||
[[Category: Plasmam membrane]] | |||
[[Category: Prenyl binding protein]] | |||
Revision as of 21:00, 1 February 2017
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. References
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