5E95

Crystal Structure of Mb(NS1)/H-Ras Complex

Summary for 5E95

• Entry DOI: 10.2210/pdb5e95/pdb
• Descriptor: Mb(NS1), GTPase HRas, GUANOSINE-5'-DIPHOSPHATE, ... (5 entities in total)
• Functional Keywords: h-ras, monobody, inhibitor, complex, signaling protein-inhibitor complex, signaling protein/inhibitor
• Biological source: Homo sapiens; More
• Total number of polymer chains: 2
• Total formula weight: 29907.47

Authors

Eguchi, R.R.,Sha, F.,Gupta, A.,Koide, A.,Koide, S. (deposition date: 2015-10-14, release date: 2016-11-02, Last modification date: 2023-09-27)

Primary citation

Spencer-Smith, R.,Koide, A.,Zhou, Y.,Eguchi, R.R.,Sha, F.,Gajwani, P.,Santana, D.,Gupta, A.,Jacobs, M.,Herrero-Garcia, E.,Cobbert, J.,Lavoie, H.,Smith, M.,Rajakulendran, T.,Dowdell, E.,Okur, M.N.,Dementieva, I.,Sicheri, F.,Therrien, M.,Hancock, J.F.,Ikura, M.,Koide, S.,O'Bryan, J.P.
Inhibition of RAS function through targeting an allosteric regulatory site.
Nat. Chem. Biol., 13:62-68, 2017

PubMed Abstract: RAS GTPases are important mediators of oncogenesis in humans. However, pharmacological inhibition of RAS has proved challenging. Here we describe a functionally critical region, located outside the effector lobe of RAS, that can be targeted for inhibition. We developed NS1, a synthetic binding protein (monobody) that bound with high affinity to both GTP- and GDP-bound states of H-RAS and K-RAS but not N-RAS. NS1 potently inhibited growth factor signaling and oncogenic H-RAS- and K-RAS-mediated signaling and transformation but did not block oncogenic N-RAS, BRAF or MEK1. NS1 bound the α4-β6-α5 region of RAS, which disrupted RAS dimerization and nanoclustering and led to blocking of CRAF-BRAF heterodimerization and activation. These results establish the importance of the α4-β6-α5 interface in RAS-mediated signaling and define a previously unrecognized site in RAS for inhibiting RAS function.

PubMed: 27820802
DOI: 10.1038/nchembio.2231

Experimental method

X-RAY DIFFRACTION (1.402 Å)