8QVU

Crystal Structure of ligand ACBI3 in complex with KRAS G12D C118S GDP and pVHL:ElonginC:ElonginB complex

8QVU の概要

• エントリーDOI: 10.2210/pdb8qvu/pdb
• 分子名称: Elongin-B, Elongin-C, von Hippel-Lindau disease tumor suppressor, ... (9 entities in total)
• 機能のキーワード: ternary complex, protac, degrader, e3 ligase, ligase, gene regulation
• 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: 139879.16

構造登録者

Wijaya, A.J.,Zollman, D.,Farnaby, W.,Ciulli, A. (登録日: 2023-10-18, 公開日: 2023-12-06, 最終更新日: 2024-10-02)

主引用文献

Popow, J.,Farnaby, W.,Gollner, A.,Kofink, C.,Fischer, G.,Wurm, M.,Zollman, D.,Wijaya, A.,Mischerikow, N.,Hasenoehrl, C.,Prokofeva, P.,Arnhof, H.,Arce-Solano, S.,Bell, S.,Boeck, G.,Diers, E.,Frost, A.B.,Goodwin-Tindall, J.,Karolyi-Oezguer, J.,Khan, S.,Klawatsch, T.,Koegl, M.,Kousek, R.,Kratochvil, B.,Kropatsch, K.,Lauber, A.A.,McLennan, R.,Olt, S.,Peter, D.,Petermann, O.,Roessler, V.,Stolt-Bergner, P.,Strack, P.,Strauss, E.,Trainor, N.,Vetma, V.,Whitworth, C.,Zhong, S.,Quant, J.,Weinstabl, H.,Kuster, B.,Ettmayer, P.,Ciulli, A.
Targeting cancer with small-molecule pan-KRAS degraders.
Science, 385:1338-1347, 2024

PubMed Abstract: Mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein are highly prevalent in cancer. However, small-molecule concepts that address oncogenic KRAS alleles remain elusive beyond replacing glycine at position 12 with cysteine (G12C), which is clinically drugged through covalent inhibitors. Guided by biophysical and structural studies of ternary complexes, we designed a heterobifunctional small molecule that potently degrades 13 out of 17 of the most prevalent oncogenic KRAS alleles. Compared with inhibition, KRAS degradation results in more profound and sustained pathway modulation across a broad range of KRAS mutant cell lines, killing cancer cells while sparing models without genetic KRAS aberrations. Pharmacological degradation of oncogenic KRAS was tolerated and led to tumor regression in vivo. Together, these findings unveil a new path toward addressing KRAS-driven cancers with small-molecule degraders.

PubMed: 39298590
DOI: 10.1126/science.adm8684

実験手法

X-RAY DIFFRACTION (2.24 Å)