5ML8

The crystal structure of PDE6D in complex to inhibitor-4

Summary for 5ML8

• Entry DOI: 10.2210/pdb5ml8/pdb
• Descriptor: Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta, ~{N}4-[(4-chlorophenyl)methyl]-~{N}4-cyclopentyl-~{N}1-(phenylmethyl)-~{N}1-(piperidin-4-ylmethyl)benzene-1,4-disulfonamide (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: 17926.03

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

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: 28106325
DOI: 10.1002/anie.201610957

Experimental method

X-RAY DIFFRACTION (2.6 Å)