9B4T

Crystal structure of the MRAS-p110alpha complex

9B4T の概要

• エントリーDOI: 10.2210/pdb9b4t/pdb
• 分子名称: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform, Ras-related protein M-Ras, (2S)-2-({2-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl}oxy)propanamide, ... (6 entities in total)
• 機能のキーワード: ras, rras3, mras, p110alpha, pik3ca, pi3kalpha, oncoprotein, pi3ka, pi3k
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 133346.60

構造登録者

Czyzyk, D.J.,Simanshu, D.K. (登録日: 2024-03-21, 公開日: 2025-01-22)

主引用文献

Czyzyk, D.,Yan, W.,Messing, S.,Gillette, W.,Tsuji, T.,Yamaguchi, M.,Furuzono, S.,Turner, D.M.,Esposito, D.,Nissley, D.V.,McCormick, F.,Simanshu, D.K.
Structural insights into isoform-specific RAS-PI3K alpha interactions and the role of RAS in PI3K alpha activation.
Nat Commun, 16:525-525, 2025

PubMed Abstract: Mutations in RAS and PI3Kα are major drivers of human cancer. Their interaction plays a crucial role in activating PI3Kα and amplifying the PI3K-AKT-mTOR pathway. Disrupting RAS-PI3Kα interaction enhances survival in lung and skin cancer models and reduces tumor growth and angiogenesis, although the structural details of this interaction remain unclear. Here, we present structures of KRAS, RRAS2, and MRAS bound to the catalytic subunit (p110α) of PI3Kα, elucidating the interaction interfaces and local conformational changes upon complex formation. Structural and mutational analyses highlighted key residues in RAS and PI3Kα impacting binding affinity and revealed isoform-specific differences at the interaction interface in RAS and PI3K isoforms, providing a rationale for their differential affinities. Notably, in the RAS-p110α complex structures, RAS interaction with p110α is limited to the RAS-binding domain and does not involve the kinase domain. This study underscores the pivotal role of the RAS-PI3Kα interaction in PI3Kα activation and provides a blueprint for designing PI3Kα isoform-specific inhibitors to disrupt this interaction.

PubMed: 39788953
DOI: 10.1038/s41467-024-55766-x

実験手法

X-RAY DIFFRACTION (2.75 Å)