PDBsum entry 4urv

Signaling protein

PDB id: 4urv

Contents

Protein chains

167 a.a.

451 a.a.

Ligands

FMT ×2

UMK

Waters ×198

PDB id:

4urv

Name:

Signaling protein

Title:

The crystal structure of h-ras and sos in complex with ligands

Structure:

Gtpase hras. Chain: r. Fragment: unp residues 1-166. Synonym: h-ras-1, ha-ras, transforming protein p21, c-h-ras, p21ras, h-ras. Engineered: yes. Son of sevenless homolog 1. Chain: s. Fragment: unp residues 564-1049.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_taxid: 562

Resolution:

2.58Å R-factor: 0.195 R-free: 0.232

Authors:

J.J.G.Winter,M.Anderson,K.Blades,C.Brassington,A.L.Breeze,C.Chresta, K.Embrey,G.Fairley,P.Faulder,M.R.V.Finlay,J.G.Kettle,T.Nowak, R.Overman,S.J.Patel,P.Perkins,L.Spadola,J.Tart,J.Tucker,G.Wrigley

Key ref:

J.J.Winter et al. (2015). Small molecule binding sites on the Ras:SOS complex can be exploited for inhibition of Ras activation. J Med Chem, 58, 2265-2274. PubMed id: 25695162 DOI: 10.1021/jm501660t

Date:

02-Jul-14 Release date: 04-Mar-15

Protein chain

P01112  (RASH_HUMAN) -  GTPase HRas from Homo sapiens

Seq: 189 a.a.

Struc: 167 a.a.

Protein chain

Q07889  (SOS1_HUMAN) -  Son of sevenless homolog 1 from Homo sapiens

Seq: 1333 a.a.

Struc: 451 a.a.

Enzyme reactions

• Enzyme class: Chain R: E.C.3.6.5.2 - small monomeric GTPase.
• Reaction: GTP + H2O = GDP + phosphate + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/jm501660t

J Med Chem 58:2265-2274 (2015)

PubMed id: 25695162

Small molecule binding sites on the Ras:SOS complex can be exploited for inhibition of Ras activation.

J.J.Winter, M.Anderson, K.Blades, C.Brassington, A.L.Breeze, C.Chresta, K.Embrey, G.Fairley, P.Faulder, M.R.Finlay, J.G.Kettle, T.Nowak, R.Overman, S.J.Patel, P.Perkins, L.Spadola, J.Tart, J.A.Tucker, G.Wrigley.

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.