5J2R
Solution structure of Ras Binding Domain (RBD) of B-Raf
Summary for 5J2R
| Entry DOI | 10.2210/pdb5j2r/pdb |
| Related | 5J17 5J18 |
| NMR Information | BMRB: 30050 |
| Descriptor | 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) |
| Functional Keywords | mapk, pi3k, protein binding |
| Biological source | Homo sapiens (Human) |
| Cellular location | Nucleus : P15056 |
| Total number of polymer chains | 1 |
| Total formula weight | 10762.57 |
| Authors | Dutta, K.,Vasquez-Del Carpio, R.,Aggarwal, A.K.,Reddy, E.P. (deposition date: 2016-03-29, release date: 2016-05-04, Last modification date: 2024-05-01) |
| 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 Cited by 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: 27104980DOI: 10.1016/j.cell.2016.03.045 PDB entries with the same primary citation |
| Experimental method | SOLUTION NMR |
Structure validation
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