4URX

The crystal structure of H-Ras and SOS in complex with ligands

Summary for 4URX

• Entry DOI: 10.2210/pdb4urx/pdb
• Related: 4URU 4URV 4URW 4URY 4URZ 4US0 4US1 4US2
• Descriptor: GTPASE HRAS, SON OF SEVENLESS HOMOLOG 1, 6-bromo-1H-indole, ... (6 entities in total)
• Functional Keywords: signaling protein
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Cell membrane. Isoform 2: Nucleus: P01112
• Total number of polymer chains: 2
• Total formula weight: 78743.19

Authors

Winter, J.J.G.,Anderson, M.,Blades, K.,Brassington, C.,Breeze, A.L.,Chresta, C.,Embrey, K.,Fairley, G.,Faulder, P.,Finlay, M.R.V.,Kettle, J.G.,Nowak, T.,Overman, R.,Patel, S.J.,Perkins, P.,Spadola, L.,Tart, J.,Tucker, J.,Wrigley, G. (deposition date: 2014-07-02, release date: 2015-03-04, Last modification date: 2024-01-10)

Primary citation

Winter, J.,Anderson, M.,Blades, K.,Chresta, C.,Embrey, K.J.,Fairley, G.,Faulder, P.,Finlay, M.R.V.,Kettle, J.G.,Nowak, T.,Overman, R.,Patel, S.J.,Perkins, P.,Spadola, L.,Tart, J.,Tucker, J.A.,Wrigley, G.
Small Molecule Binding Sites on the Ras:SOS Complex Can be Exploited for Inhibition of Ras Activation.
J.Med.Chem., 58:2265-, 2015

PubMed Abstract: Constitutively active mutant KRas displays a reduced rate of GTP hydrolysis via both intrinsic and GTPase-activating protein-catalyzed mechanisms, resulting in the perpetual activation of Ras pathways. We describe a fragment screening campaign using X-ray crystallography that led to the discovery of three fragment binding sites on the Ras:SOS complex. The identification of tool compounds binding at each of these sites allowed exploration of two new approaches to Ras pathway inhibition by stabilizing or covalently modifying the Ras:SOS complex to prevent the reloading of Ras with GTP. Initially, we identified ligands that bound reversibly to the Ras:SOS complex in two distinct sites, but these compounds were not sufficiently potent inhibitors to validate our stabilization hypothesis. We conclude by demonstrating that covalent modification of Cys118 on Ras leads to a novel mechanism of inhibition of the SOS-mediated interaction between Ras and Raf and is effective at inhibiting the exchange of labeled GDP in both mutant (G12C and G12V) and wild type Ras.

PubMed: 25695162
DOI: 10.1021/JM501660T

Experimental method

X-RAY DIFFRACTION (2.49 Å)