7Q9U

Crystal structure of the high affinity KRas mutant PDE6D complex

これはPDB形式変換不可エントリーです。

7Q9U の概要

• エントリーDOI: 10.2210/pdb7q9u/pdb
• 分子名称: GTPase KRas, Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta, GUANOSINE-5'-DIPHOSPHATE, ... (7 entities in total)
• 機能のキーワード: cancer, drug discovery, complex, signaling protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 78923.69

構造登録者

Yelland, T.,Ismail, I. (登録日: 2021-11-14, 公開日: 2022-01-26, 最終更新日: 2024-01-31)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.238 Å)