PDBsum entry 4nyj

Signaling protein

PDB id: 4nyj

Contents

Protein chains

166 a.a.

468 a.a.

Ligands

GNP

2PZ

Metals

_MG

Waters ×125

PDB id:

4nyj

Name:

Signaling protein

Title:

Approach for targeting ras with small molecules that activate sos- mediated nucleotide exchange

Structure:

Gtpase hras. Chain: q. Synonym: h-ras-1, ha-ras, transforming protein p21, c-h-ras, p21ras, gtpase hras, n-terminally processed. Engineered: yes. Mutation: yes. Gtpase hras. Chain: r. Synonym: h-ras-1, ha-ras, transforming protein p21, c-h-ras, p21ras,

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: hras, hras1. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: sos1. Expression_system_taxid: 562

Resolution:

2.85Å R-factor: 0.157 R-free: 0.187

Authors:

M.C.Burns,Q.Sun,J.Phan,S.W.Fesik

Key ref:

M.C.Burns et al. (2014). Approach for targeting Ras with small molecules that activate SOS-mediated nucleotide exchange. Proc Natl Acad Sci U S A, 111, 3401-3406. PubMed id: 24550516 DOI: 10.1073/pnas.1315798111

Date:

10-Dec-13 Release date: 12-Mar-14

Protein chains

P01112  (RASH_HUMAN) -  GTPase HRas from Homo sapiens

Seq: 189 a.a.

Struc: 166 a.a.*

Protein chain

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

Seq: 1333 a.a.

Struc: 468 a.a.

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

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

GTP + H2O = GDP (Bound ligand (Het Group name = GNP) matches with 81.82% similarity) + phosphate + H(+)

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

reference

DOI no: 10.1073/pnas.1315798111

Proc Natl Acad Sci U S A 111:3401-3406 (2014)

PubMed id: 24550516

Approach for targeting Ras with small molecules that activate SOS-mediated nucleotide exchange.

M.C.Burns, Q.Sun, R.N.Daniels, D.Camper, J.P.Kennedy, J.Phan, E.T.Olejniczak, T.Lee, A.G.Waterson, O.W.Rossanese, S.W.Fesik.

ABSTRACT

Aberrant activation of the small GTPase Ras by oncogenic mutation or constitutively active upstream receptor tyrosine kinases results in the deregulation of cellular signals governing growth and survival in ∼30% of all human cancers. However, the discovery of potent inhibitors of Ras has been difficult to achieve. Here, we report the identification of small molecules that bind to a unique pocket on the Ras:Son of Sevenless (SOS):Ras complex, increase the rate of SOS-catalyzed nucleotide exchange in vitro, and modulate Ras signaling pathways in cells. X-ray crystallography of Ras:SOS:Ras in complex with these molecules reveals that the compounds bind in a hydrophobic pocket in the CDC25 domain of SOS adjacent to the Switch II region of Ras. The structure-activity relationships exhibited by these compounds can be rationalized on the basis of multiple X-ray cocrystal structures. Mutational analyses confirmed the functional relevance of this binding site and showed it to be essential for compound activity. These molecules increase Ras-GTP levels and disrupt MAPK and PI3K signaling in cells at low micromolar concentrations. These small molecules represent tools to study the acute activation of Ras and highlight a pocket on SOS that may be exploited to modulate Ras signaling.