4D9T

Rsk2 C-terminal Kinase Domain with inhibitor (E)-methyl 3-(4-amino-7-(3-hydroxypropyl)-5-p-tolyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-2-cyanoacrylate


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.267 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.221 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Reversible targeting of noncatalytic cysteines with chemically tuned electrophiles.

Serafimova, I.M.Pufall, M.A.Krishnan, S.Duda, K.Cohen, M.S.Maglathlin, R.L.McFarland, J.M.Miller, R.M.Frodin, M.Taunton, J.

(2012) Nat Chem Biol 8: 471-476

  • DOI: https://doi.org/10.1038/nchembio.925
  • Primary Citation of Related Structures:  
    4D9T, 4D9U

  • PubMed Abstract: 

    Targeting noncatalytic cysteine residues with irreversible acrylamide-based inhibitors is a powerful approach for enhancing pharmacological potency and selectivity. Nevertheless, concerns about off-target modification motivate the development of reversible cysteine-targeting strategies. Here we show that electron-deficient olefins, including acrylamides, can be tuned to react with cysteine thiols in a rapidly reversible manner. Installation of a nitrile group increased the olefins' intrinsic reactivity, but, paradoxically, eliminated the formation of irreversible adducts. Incorporation of these electrophiles into a noncovalent kinase-recognition scaffold produced slowly dissociating, covalent inhibitors of the p90 ribosomal protein S6 kinase RSK2. A cocrystal structure revealed specific noncovalent interactions that stabilize the complex by positioning the electrophilic carbon near the targeted cysteine. Disruption of these interactions by protein unfolding or proteolysis promoted instantaneous cleavage of the covalent bond. Our results establish a chemistry-based framework for engineering sustained covalent inhibition without accumulating permanently modified proteins and peptides.


  • Organizational Affiliation

    Graduate Program in Chemistry and Chemical Biology, University of California-San Francisco, San Francisco, California, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Ribosomal protein S6 kinase alpha-3342Homo sapiensMutation(s): 0 
Gene Names: ISPK1MAPKAPK1BRPS6KA3RSK2
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for P51812 (Homo sapiens)
Explore P51812 
Go to UniProtKB:  P51812
PHAROS:  P51812
GTEx:  ENSG00000177189 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP51812
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
0JG
Query on 0JG

Download Ideal Coordinates CCD File 
B [auth A]methyl (2S)-3-{4-amino-7-[(1E)-3-hydroxyprop-1-en-1-yl]-5-(4-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-2-cyanopropanoate
C21 H21 N5 O3
ZJERBAYUHUAUBE-GZTQLTBSSA-N
NA
Query on NA

Download Ideal Coordinates CCD File 
C [auth A]SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.267 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.221 
  • Space Group: P 41 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 46.7α = 90
b = 46.7β = 90
c = 294.1γ = 90
Software Package:
Software NamePurpose
XSCALEdata scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
Blu-Icedata collection
XDSdata reduction
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: 2012-04-25
    Type: Initial release
  • Version 1.1: 2012-05-16
    Changes: Database references