5ML2

The crystal structure of PDE6D in complex with inhibitor-3


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.227 
  • R-Value Work: 0.202 
  • R-Value Observed: 0.203 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

A PDE6 delta-KRas Inhibitor Chemotype with up to Seven H-Bonds and Picomolar Affinity that Prevents Efficient Inhibitor Release by Arl2.

Martin-Gago, P.Fansa, E.K.Klein, C.H.Murarka, S.Janning, P.Schurmann, M.Metz, M.Ismail, S.Schultz-Fademrecht, C.Baumann, M.Bastiaens, P.I.Wittinghofer, A.Waldmann, H.

(2017) Angew Chem Int Ed Engl 56: 2423-2428

  • DOI: https://doi.org/10.1002/anie.201610957
  • Primary Citation of Related Structures:  
    5ML2, 5ML3, 5ML4, 5ML6, 5ML8

  • PubMed Abstract: 

    Small-molecule inhibition of the interaction between the KRas oncoprotein and the chaperone PDE6δ impairs KRas spatial organization and signaling in cells. However, despite potent binding in vitro (K D <10 nm), interference with Ras signaling and growth inhibition require 5-20 μm compound concentrations. We demonstrate that these findings can be explained by fast release of high-affinity inhibitors from PDE6δ by the release factor Arl2. This limitation is overcome by novel highly selective inhibitors that bind to PDE6δ with up to 7 hydrogen bonds, resulting in picomolar affinity. Their release by Arl2 is greatly decreased, and representative compounds selectively inhibit growth of KRas mutated and -dependent cells with the highest activity recorded yet. Our findings indicate that very potent inhibitors of the KRas-PDE6δ interaction may impair the growth of tumors driven by oncogenic KRas.


  • Organizational Affiliation

    Department of Chemical Biology, Max Planck Institute of Molecular Physiology, 44227, Dortmund, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit deltaA [auth B]149Homo sapiensMutation(s): 0 
Gene Names: PDE6DPDED
UniProt & NIH Common Fund Data Resources
Find proteins for O43924 (Homo sapiens)
Explore O43924 
Go to UniProtKB:  O43924
PHAROS:  O43924
GTEx:  ENSG00000156973 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO43924
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NH6
Query on NH6

Download Ideal Coordinates CCD File 
B
~{N}1-[(4-chlorophenyl)methyl]-~{N}1-cyclopentyl-~{N}4-(phenylmethyl)benzene-1,4-disulfonamide
C25 H27 Cl N2 O4 S2
CWMNFAGFCBOHSI-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
NH6 Binding MOAD:  5ML2 Kd: 13 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.227 
  • R-Value Work: 0.202 
  • R-Value Observed: 0.203 
  • Space Group: P 32 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 55.65α = 90
b = 55.65β = 90
c = 115.34γ = 120
Software Package:
Software NamePurpose
XSCALEdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
MOLREPphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
SFBGermanySFB 642
European Research CouncilGermanyERC Grant 268782

Revision History  (Full details and data files)

  • Version 1.0: 2017-02-01
    Type: Initial release
  • Version 1.1: 2017-02-22
    Changes: Database references
  • Version 1.2: 2024-01-17
    Changes: Author supporting evidence, Data collection, Database references, Refinement description