RCSB PDB - 6D56: Ras:SOS:Ras in complex with a small molecule activator

 6D56

Ras:SOS:Ras in complex with a small molecule activator


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.68 Å
  • R-Value Free: 0.171 
  • R-Value Work: 0.159 
  • R-Value Observed: 0.160 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted GNPClick on this verticalbar to view detailsBest fitted FVMClick on this verticalbar to view details

This is version 1.4 of the entry. See complete history


Literature

Discovery and Structure-Based Optimization of Benzimidazole-Derived Activators of SOS1-Mediated Nucleotide Exchange on RAS.

Hodges, T.R.Abbott, J.R.Little, A.J.Sarkar, D.Salovich, J.M.Howes, J.E.Akan, D.T.Sai, J.Arnold, A.L.Browning, C.Burns, M.C.Sobolik, T.Sun, Q.Beesetty, Y.Coker, J.A.Scharn, D.Stadtmueller, H.Rossanese, O.W.Phan, J.Waterson, A.G.McConnell, D.B.Fesik, S.W.

(2018) J Med Chem 61: 8875-8894

  • DOI: https://doi.org/10.1021/acs.jmedchem.8b01108
  • Primary Citation of Related Structures:  
    6D55, 6D56, 6D59, 6D5E, 6D5G, 6D5H, 6D5J, 6D5L, 6D5M, 6D5V, 6D5W

  • PubMed Abstract: 

    Son of sevenless homologue 1 (SOS1) is a guanine nucleotide exchange factor that catalyzes the exchange of GDP for GTP on RAS. In its active form, GTP-bound RAS is responsible for numerous critical cellular processes. Aberrant RAS activity is involved in ∼30% of all human cancers; hence, SOS1 is an attractive therapeutic target for its role in modulating RAS activation. Here, we describe a new series of benzimidazole-derived SOS1 agonists. Using structure-guided design, we discovered small molecules that increase nucleotide exchange on RAS in vitro at submicromolar concentrations, bind to SOS1 with low double-digit nanomolar affinity, rapidly enhance cellular RAS-GTP levels, and invoke biphasic signaling changes in phosphorylation of ERK 1/2. These compounds represent the most potent series of SOS1 agonists reported to date.


  • Organizational Affiliation

    Boehringer Ingelheim RCV GmbH & Co. KG , Doktor-Boehringer-Gasse 5-11 , 1120 Vienna , Austria.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
GTPase HRas167Homo sapiensMutation(s): 0 
Gene Names: HRASHRAS1
EC: 3.6.5.2
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
Son of sevenless homolog 1482Homo 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
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
GTPase HRas167Homo sapiensMutation(s): 0 
Gene Names: HRASHRAS1
EC: 3.6.5.2
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
Small Molecules
Ligands 6 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
GNP
Query on GNP

Download Ideal Coordinates CCD File 
D [auth A]PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER
C10 H17 N6 O13 P3
UQABYHGXWYXDTK-UUOKFMHZSA-N
FVM
Query on FVM

Download Ideal Coordinates CCD File 
F [auth B]6-chloro-2-(2,6-diazaspiro[3.3]heptan-2-yl)-4-(3,5-dimethyl-1H-pyrazol-4-yl)-1-[(4-fluoro-3,5-dimethylphenyl)methyl]-1H-benzimidazole
C26 H28 Cl F N6
WYYRAJGTUGUYGY-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
L [auth B],
M [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
FMT
Query on FMT

Download Ideal Coordinates CCD File 
G [auth B]
H [auth B]
I [auth B]
J [auth B]
K [auth B]
FORMIC ACID
C H2 O2
BDAGIHXWWSANSR-UHFFFAOYSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
E [auth A]MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
NA
Query on NA

Download Ideal Coordinates CCD File 
O [auth C]SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
CSO
Query on CSO
A
L-PEPTIDE LINKINGC3 H7 N O3 SCYS
Binding Affinity Annotations 
IDSourceBinding Affinity
FVM BindingDB:  6D56 Kd: 9 (nM) from 1 assay(s)
EC50: min: 1.41e+4, max: 2.11e+4 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.68 Å
  • R-Value Free: 0.171 
  • R-Value Work: 0.159 
  • R-Value Observed: 0.160 
  • Space Group: I 4 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 183.621α = 90
b = 183.621β = 90
c = 178.738γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted GNPClick on this verticalbar to view detailsBest fitted FVMClick on this verticalbar to view details

Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
United StatesLustgarten

Revision History  (Full details and data files)

  • Version 1.0: 2018-09-19
    Type: Initial release
  • Version 1.1: 2018-11-07
    Changes: Data collection, Database references
  • Version 1.2: 2023-10-04
    Changes: Data collection, Database references, Derived calculations, Refinement description
  • Version 1.3: 2023-11-15
    Changes: Data collection
  • Version 1.4: 2024-10-30
    Changes: Structure summary