9RKC

Crystal Structure of ACBI4-mediated ternary complex of KRAS G12D C118S GDP with pVHL:ElonginC:ElonginB

これはPDB形式変換不可エントリーです。

9RKC の概要

• エントリーDOI: 10.2210/pdb9rkc/pdb
• 分子名称: Elongin-B, Elongin-C, von Hippel-Lindau disease tumor suppressor, ... (8 entities in total)
• 機能のキーワード: kras, tpd, protac, vhl, ternary complex, oncoprotein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 124467.60

構造登録者

Karolak, N.K.,Ciulli, A. (登録日: 2025-06-13, 公開日: 2025-11-12)

主引用文献

Vetma, V.,Puoti, I.,Karolak, N.K.,Chakraborti, S.,Diers, E.,Girardi, E.,Khan, S.,Kidd, G.,Kropatsch, K.G.,Mclennan, R.,O'Connor, S.,Samwer, M.,Trainor, N.,Whitworth, C.,Wijaya, A.J.,Wong, J.Y.F.,Zollman, D.,Farnaby, W.,Popow, J.,Ciulli, A.,Ettmayer, P.,McAulay, K.
Identification of a Highly Cooperative PROTAC Degrader Targeting GTP-Loaded KRAS(On) Alleles.
J.Am.Chem.Soc., 2025

PubMed Abstract: Kirsten rat sarcoma viral oncogene homologue (KRAS) is a frequently mutated oncogene in multiple types of cancer and is a high priority target for oncology drug development. There are many different KRAS mutations, including mutations that favor the GTP-loaded hydrolysis-incompetent "active" state of KRAS, KRAS(on), that can lead to tumorigenesis. However, small molecule interventions thus far have predominantly targeted single mutations of "inactive" GDP-loaded KRAS, KRAS(off), such as KRAS. Here, we address this gap through the development of heterobifunctional VHL-based PROTACs capable of engaging and degrading KRAS(on), thus addressing a wider range of KRAS mutations. By studying ternary complex affinity, stability, and binding modes using SPR and X-ray cocrystal structures, we identified PROTACs that exhibit high positive cooperativity in forming ternary complexes with VHL and GCP-loaded KRAS as representative of KRAS(on) variants. Degrader activity profiling in relevant cancer cells supported the discovery of ACBI4, a PROTAC which forms a highly stable and cooperative ternary complex between VHL and GTP-bound KRAS and which potently degrades KRAS, leading to antiproliferative effect in KRAS mutant-driven cancer cells. ACBI4 provides a new chemical tool for studying the impact of degrading KRAS(on) mutants, which is not possible with current pan-KRAS inhibitors or degraders.

PubMed: 41166656
DOI: 10.1021/jacs.5c10354

実験手法

X-RAY DIFFRACTION (2.19 Å)