View source for 5ml8


==The crystal structure of PDE6D in complex to inhibitor-4==
<StructureSection load='5ml8' size='340' side='right'caption='[[5ml8]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5ml8]] 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=5ML8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5ML8 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.6&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=V98:~{N}4-[(4-CHLOROPHENYL)METHYL]-~{N}4-CYCLOPENTYL-~{N}1-(PHENYLMETHYL)-~{N}1-(PIPERIDIN-4-YLMETHYL)BENZENE-1,4-DISULFONAMIDE'>V98</scene></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=5ml8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ml8 OCA], [https://pdbe.org/5ml8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ml8 RCSB], [https://www.ebi.ac.uk/pdbsum/5ml8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ml8 ProSAT]</span></td></tr>
</table>
== Function ==
[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;">
== 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 &lt;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&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5ml8" style="background-color:#fffaf0;"></div>

==See Also==
*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Fansa EK]]
[[Category: Martin-Gago P]]
[[Category: Waldmann H]]
[[Category: Wittinghofer A]]