5ml2: Difference between revisions

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~~'''Unreleased structure'''~~

The ~~entry~~ 5ml2 is ~~ON HOLD~~

==The crystal structure of PDE6D in complex with inhibitor-3==

== Structural highlights ==

<table><tr><td colspan='2'>[[5ml2]] 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=5ML2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5ML2 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]] 1.6Å</td></tr>

<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NH6:~{N}1-[(4-CHLOROPHENYL)METHYL]-~{N}1-CYCLOPENTYL-~{N}4-(PHENYLMETHYL)BENZENE-1,4-DISULFONAMIDE'>NH6</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=5ml2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ml2 OCA], [https://pdbe.org/5ml2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ml2 RCSB], [https://www.ebi.ac.uk/pdbsum/5ml2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ml2 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).

== 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.

~~Authors: Fansa, E.K~~., Martin-Gago, P., ~~Waldmann~~, H., Wittinghofer, A.

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>

~~Description: The crystal structure~~ of ~~PDE6D in complex with inhibitor~~-3

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>

[[Category: ~~Unreleased~~ Structures]]

</div>

[[Category: ~~Waldmann, H~~]]

[[Category: Martin-Gago, P]]

[[Category: ~~Wittinghofer, A~~]]

==See Also==

[[Category: ~~Fansa, E.K~~]]

*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]]

== References ==

__TOC__

</StructureSection>

[[Category: Homo sapiens]]

[[Category: Large Structures]]

[[Category: Fansa EK]]

[[Category: Martin-Gago P]]

[[Category: Waldmann H]]

[[Category: Wittinghofer A]]

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@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 5ml2 is ON HOLD
+==The crystal structure of PDE6D in complex with inhibitor-3==
+<StructureSection load='5ml2' size='340' side='right'caption='[[5ml2]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5ml2]] 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=5ML2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5ML2 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]] 1.6&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NH6:~{N}1-[(4-CHLOROPHENYL)METHYL]-~{N}1-CYCLOPENTYL-~{N}4-(PHENYLMETHYL)BENZENE-1,4-DISULFONAMIDE'>NH6</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=5ml2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ml2 OCA], [https://pdbe.org/5ml2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ml2 RCSB], [https://www.ebi.ac.uk/pdbsum/5ml2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ml2 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.
-Authors: Fansa, E.K., Martin-Gago, P., Waldmann, H., Wittinghofer, A.
+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>
-Description: The crystal structure of PDE6D in complex with inhibitor-3
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Waldmann, H]]
+<div class="pdbe-citations 5ml2" style="background-color:#fffaf0;"></div>
-[[Category: Martin-Gago, P]]
-[[Category: Wittinghofer, A]]
+==See Also==
-[[Category: Fansa, E.K]]
+*[[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]]