3U4W

Src in complex with DNA-templated macrocyclic inhibitor MC4b


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.186 
  • R-Value Work: 0.162 
  • R-Value Observed: 0.163 

wwPDB Validation   3D Report Full Report


This is version 2.0 of the entry. See complete history


Literature

Highly specific, bisubstrate-competitive Src inhibitors from DNA-templated macrocycles.

Georghiou, G.Kleiner, R.E.Pulkoski-Gross, M.Liu, D.R.Seeliger, M.A.

(2012) Nat Chem Biol 8: 366-374

  • DOI: https://doi.org/10.1038/nchembio.792
  • Primary Citation of Related Structures:  
    3U4W, 3U51

  • PubMed Abstract: 

    Protein kinases are attractive therapeutic targets, but their high sequence and structural conservation complicates the development of specific inhibitors. We recently identified, in a DNA-templated macrocycle library, inhibitors with unusually high selectivity among Src-family kinases. Starting from these compounds, we developed and characterized in molecular detail potent macrocyclic inhibitors of Src kinase and its cancer-associated 'gatekeeper' mutant. We solved two cocrystal structures of macrocycles bound to Src kinase. These structures reveal the molecular basis of the combined ATP- and substrate peptide-competitive inhibitory mechanism and the remarkable kinase specificity of the compounds. The most potent compounds inhibit Src activity in cultured mammalian cells. Our work establishes that macrocycles can inhibit protein kinases through a bisubstrate-competitive mechanism with high potency and exceptional specificity, reveals the precise molecular basis for their desirable properties and provides new insights into the development of Src-specific inhibitors with potential therapeutic relevance.


  • Organizational Affiliation

    Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Proto-oncogene tyrosine-protein kinase Src275Gallus gallusMutation(s): 0 
Gene Names: SRC
EC: 2.7.10.2
UniProt
Find proteins for P00523 (Gallus gallus)
Explore P00523 
Go to UniProtKB:  P00523
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00523
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
macrocyclic inhibitor MC4B5N/AMutation(s): 0 
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Modified Residues  2 Unique
IDChains TypeFormula2D DiagramParent
ALC
Query on ALC
B
L-PEPTIDE LINKINGC9 H17 N O2ALA
DAB
Query on DAB
B
L-PEPTIDE LINKINGC4 H10 N2 O2ALA
Binding Affinity Annotations 
IDSourceBinding Affinity
08L Binding MOAD:  3U4W IC50: 130 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.186 
  • R-Value Work: 0.162 
  • R-Value Observed: 0.163 
  • Space Group: P 3 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 143.61α = 90
b = 143.61β = 90
c = 41.51γ = 120
Software Package:
Software NamePurpose
SCALAdata scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACTdata extraction
CBASSdata collection
MOSFLMdata reduction

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-02-22
    Type: Initial release
  • Version 1.1: 2012-03-07
    Changes: Database references
  • Version 1.2: 2012-04-04
    Changes: Database references
  • Version 1.3: 2012-12-12
    Changes: Other
  • Version 1.4: 2020-09-23
    Changes: Derived calculations
  • Version 1.5: 2023-09-13
    Changes: Data collection, Database references, Refinement description
  • Version 2.0: 2023-11-15
    Changes: Atomic model, Data collection, Derived calculations