7QF9

Crystal structure of PDE6D bound to HRas peptide

This is a non-PDB format compatible entry.

Summary for 7QF9

• Entry DOI: 10.2210/pdb7qf9/pdb
• Descriptor: Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta, HRas peptide, FARNESYL, ... (6 entities in total)
• Functional Keywords: complex, trafficking, transport protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 36465.06

Authors

Yelland, T.,Ismail, I. (deposition date: 2021-12-05, release date: 2022-02-09, Last modification date: 2025-04-09)

Primary citation

Yelland, T.,Garcia, E.,Parry, C.,Kowalczyk, D.,Wojnowska, M.,Gohlke, A.,Zalar, M.,Cameron, K.,Goodwin, G.,Yu, Q.,Zhu, P.C.,ElMaghloob, Y.,Pugliese, A.,Archibald, L.,Jamieson, A.,Chen, Y.X.,McArthur, D.,Bower, J.,Ismail, S.
Stabilization of the RAS:PDE6D Complex Is a Novel Strategy to Inhibit RAS Signaling.
J.Med.Chem., 65:1898-1914, 2022

PubMed Abstract: RAS is a major anticancer drug target which requires membrane localization to activate downstream signal transduction. The direct inhibition of RAS has proven to be challenging. Here, we present a novel strategy for targeting RAS by stabilizing its interaction with the prenyl-binding protein PDE6D and disrupting its localization. Using rationally designed RAS point mutations, we were able to stabilize the RAS:PDE6D complex by increasing the affinity of RAS for PDE6D, which resulted in the redirection of RAS to the cytoplasm and the primary cilium and inhibition of oncogenic RAS/ERK signaling. We developed an SPR fragment screening and identified fragments that bind at the KRAS:PDE6D interface, as shown through cocrystal structures. Finally, we show that the stoichiometric ratios of KRAS:PDE6D vary in different cell lines, suggesting that the impact of this strategy might be cell-type-dependent. This study forms the foundation from which a potential anticancer small-molecule RAS:PDE6D complex stabilizer could be developed.

PubMed: 35104933
DOI: 10.1021/acs.jmedchem.1c01265

Experimental method

X-RAY DIFFRACTION (1.95 Å)