5J2R

Solution structure of Ras Binding Domain (RBD) of B-Raf

5J2R の概要

• エントリーDOI: 10.2210/pdb5j2r/pdb
• 関連するPDBエントリー: 5J17 5J18
• NMR情報: BMRB: 30050
• 分子名称: Serine/threonine-protein kinase B-raf, N-[2-methoxy-5-({[(E)-2-(2,4,6-trimethoxyphenyl)ethenyl]sulfonyl}methyl)phenyl]glycine (2 entities in total)
• 機能のキーワード: mapk, pi3k, protein binding
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus : P15056
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 10762.57

構造登録者

Dutta, K.,Vasquez-Del Carpio, R.,Aggarwal, A.K.,Reddy, E.P. (登録日: 2016-03-29, 公開日: 2016-05-04, 最終更新日: 2024-05-01)

主引用文献

Athuluri-Divakar, S.K.,Vasquez-Del Carpio, R.,Dutta, K.,Baker, S.J.,Cosenza, S.C.,Basu, I.,Gupta, Y.K.,Reddy, M.V.,Ueno, L.,Hart, J.R.,Vogt, P.K.,Mulholland, D.,Guha, C.,Aggarwal, A.K.,Reddy, E.P.
A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling.
Cell, 165:643-655, 2016

PubMed Abstract: Oncogenic activation of RAS genes via point mutations occurs in 20%-30% of human cancers. The development of effective RAS inhibitors has been challenging, necessitating new approaches to inhibit this oncogenic protein. Functional studies have shown that the switch region of RAS interacts with a large number of effector proteins containing a common RAS-binding domain (RBD). Because RBD-mediated interactions are essential for RAS signaling, blocking RBD association with small molecules constitutes an attractive therapeutic approach. Here, we present evidence that rigosertib, a styryl-benzyl sulfone, acts as a RAS-mimetic and interacts with the RBDs of RAF kinases, resulting in their inability to bind to RAS, disruption of RAF activation, and inhibition of the RAS-RAF-MEK pathway. We also find that ribosertib binds to the RBDs of Ral-GDS and PI3Ks. These results suggest that targeting of RBDs across multiple signaling pathways by rigosertib may represent an effective strategy for inactivation of RAS signaling.

PubMed: 27104980
DOI: 10.1016/j.cell.2016.03.045

実験手法

SOLUTION NMR