5ML6
The crystal structure of PDE6D in complex to inhibitor-8
Summary for 5ML6
| Entry DOI | 10.2210/pdb5ml6/pdb |
| Descriptor | Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta, 2-azanyl-4-[[[4-[(4-chlorophenyl)methyl-cyclopentyl-sulfamoyl]phenyl]sulfonyl-(piperidin-4-ylmethyl)amino]methyl]benzoic acid (3 entities in total) |
| Functional Keywords | prenyl binding protein, farnesylated kras, plasma membrane, arl2, lipid binding protein |
| Biological source | Homo sapiens (Human) |
| Cellular location | Cytoplasm, cytosol : O43924 |
| Total number of polymer chains | 1 |
| Total formula weight | 17985.05 |
| Authors | Fansa, E.K.,Martin-gago, P.,Waldmann, H.,Wittinghofer, A. (deposition date: 2016-12-06, release date: 2017-02-01, Last modification date: 2024-01-17) |
| Primary citation | Martin-Gago, P.,Fansa, E.K.,Klein, C.H.,Murarka, S.,Janning, P.,Schurmann, M.,Metz, M.,Ismail, S.,Schultz-Fademrecht, C.,Baumann, M.,Bastiaens, P.I.,Wittinghofer, A.,Waldmann, H. A PDE6 delta-KRas Inhibitor Chemotype with up to Seven H-Bonds and Picomolar Affinity that Prevents Efficient Inhibitor Release by Arl2. Angew. Chem. Int. Ed. Engl., 56:2423-2428, 2017 Cited by PubMed Abstract: Small-molecule inhibition of the interaction between the KRas oncoprotein and the chaperone PDE6δ impairs KRas spatial organization and signaling in cells. However, despite potent binding in vitro (K <10 nm), interference with Ras signaling and growth inhibition require 5-20 μm compound concentrations. We demonstrate that these findings can be explained by fast release of high-affinity inhibitors from PDE6δ by the release factor Arl2. This limitation is overcome by novel highly selective inhibitors that bind to PDE6δ 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-PDE6δ interaction may impair the growth of tumors driven by oncogenic KRas. PubMed: 28106325DOI: 10.1002/anie.201610957 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.87 Å) |
Structure validation
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