4JV8

The crystal structure of PDE6D in complex with rac-S1

Summary for 4JV8

• Entry DOI: 10.2210/pdb4jv8/pdb
• Related: 4JV6 4JVB 4JVF
• Descriptor: Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta, (6R)-6-(pyridin-2-yl)-5,6-dihydrobenzimidazo[1,2-c]quinazoline (3 entities in total)
• Functional Keywords: immunoglobulin-like beta-sandwich, gdi-like solubilizing factor, prenyl binding, protein binding-inhibitor complex, protein binding/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 18181.80

Authors

Gunther, Z.,Papke, B.,Ismail, S.,Vartak, N.,Chandra, A.,Hoffmann, M.,Hahn, S.,Triola, G.,Wittinghofer, A.,Bastiaens, P.,Waldmann, H. (deposition date: 2013-03-25, release date: 2013-05-22, Last modification date: 2023-09-20)

Primary citation

Zimmermann, G.,Papke, B.,Ismail, S.,Vartak, N.,Chandra, A.,Hoffmann, M.,Hahn, S.A.,Triola, G.,Wittinghofer, A.,Bastiaens, P.I.,Waldmann, H.
Small molecule inhibition of the KRAS PDEd interaction impairs oncogenic KRAS signalling
Nature, 497:638-642, 2013

PubMed Abstract: The KRAS oncogene product is considered a major target in anticancer drug discovery. However, direct interference with KRAS signalling has not yet led to clinically useful drugs. Correct localization and signalling by farnesylated KRAS is regulated by the prenyl-binding protein PDEδ, which sustains the spatial organization of KRAS by facilitating its diffusion in the cytoplasm. Here we report that interfering with binding of mammalian PDEδ to KRAS by means of small molecules provides a novel opportunity to suppress oncogenic RAS signalling by altering its localization to endomembranes. Biochemical screening and subsequent structure-based hit optimization yielded inhibitors of the KRAS-PDEδ interaction that selectively bind to the prenyl-binding pocket of PDEδ with nanomolar affinity, inhibit oncogenic RAS signalling and suppress in vitro and in vivo proliferation of human pancreatic ductal adenocarcinoma cells that are dependent on oncogenic KRAS. Our findings may inspire novel drug discovery efforts aimed at the development of drugs targeting oncogenic RAS.

PubMed: 23698361
DOI: 10.1038/nature12205

Experimental method

X-RAY DIFFRACTION (1.45 Å)