4NYM

Approach for Targeting Ras with Small Molecules that Activate SOS-Mediated Nucleotide Exchange


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.55 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.158 
  • R-Value Observed: 0.161 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

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

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

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

  • DOI: https://doi.org/10.1073/pnas.1315798111
  • Primary Citation of Related Structures:  
    4NYI, 4NYJ, 4NYM

  • PubMed 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.


  • Organizational Affiliation

    Departments of Biochemistry, Pharmacology, and Chemistry, Vanderbilt University School of Medicine, Nashville, TN 37232.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
GTPase HRasA [auth Q]166Homo sapiensMutation(s): 1 
Gene Names: HRASHRAS1
UniProt & NIH Common Fund Data Resources
Find proteins for P01112 (Homo sapiens)
Explore P01112 
Go to UniProtKB:  P01112
PHAROS:  P01112
GTEx:  ENSG00000174775 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP01112
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
GTPase HRasB [auth R]166Homo sapiensMutation(s): 0 
Gene Names: HRASHRAS1
UniProt & NIH Common Fund Data Resources
Find proteins for P01112 (Homo sapiens)
Explore P01112 
Go to UniProtKB:  P01112
PHAROS:  P01112
GTEx:  ENSG00000174775 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP01112
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Son of sevenless homolog 1C [auth S]481Homo sapiensMutation(s): 0 
Gene Names: SOS1
UniProt & NIH Common Fund Data Resources
Find proteins for Q07889 (Homo sapiens)
Explore Q07889 
Go to UniProtKB:  Q07889
PHAROS:  Q07889
GTEx:  ENSG00000115904 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ07889
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
GNP
Query on GNP

Download Ideal Coordinates CCD File 
E [auth Q]PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER
C10 H17 N6 O13 P3
UQABYHGXWYXDTK-UUOKFMHZSA-N
RND
Query on RND

Download Ideal Coordinates CCD File 
F [auth S]N-[1-(1H-indol-3-ylmethyl)piperidin-4-yl]-L-tryptophanamide
C25 H29 N5 O
YLGBZXMOCLUOKZ-QFIPXVFZSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
D [auth Q]MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.55 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.158 
  • R-Value Observed: 0.161 
  • Space Group: I 4 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 186.805α = 90
b = 186.805β = 90
c = 178.684γ = 90
Software Package:
Software NamePurpose
MAR345dtbdata collection
PHENIXmodel building
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-03-12
    Type: Initial release
  • Version 1.1: 2014-03-19
    Changes: Database references
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description