5J17

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

Summary for 5J17

• Entry DOI: 10.2210/pdb5j17/pdb
• Related: 5J18 5J2R
• NMR Information: BMRB: 30047
• Descriptor: Serine/threonine-protein kinase B-raf (1 entity in total)
• Functional Keywords: mapk, pi3k, protein binding
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 10311.08

Authors

Dutta, K.,Vasquez-Del Carpio, R.,Aggarwal, A.K.,Reddy, E.P. (deposition date: 2016-03-29, release date: 2016-10-05, Last modification date: 2024-05-15)

Primary citation

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

Experimental method

SOLUTION NMR