3C9W

Crystal Structure of ERK-2 with hypothemycin covalently bound


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.274 
  • R-Value Work: 0.197 
  • R-Value Observed: 0.201 

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This is version 1.3 of the entry. See complete history


Literature

Molecular modeling and crystal structure of ERK2-hypothemycin complexes

Rastelli, G.Rosenfeld, R.Reid, R.Santi, D.V.

(2008) J Struct Biol 164: 18-23

  • DOI: https://doi.org/10.1016/j.jsb.2008.05.002
  • Primary Citation of Related Structures:  
    3C9W

  • PubMed Abstract: 

    Resorcylic acid lactones containing a cis-enone-such as hypothemycin-are susceptible to Michael addition reactions and are potent and specific inhibitors of about 45 of the known Ser/Thr/Tyr protein kinases. These inhibitors bind reversibly, and then form a covalent adduct with a completely conserved cysteine in the ATP binding site of their target kinases. As a paradigm for the structures of the cis-enone resorcylic acid lactone complexes with this subset of kinases, we have modeled the structure of ERK2-hypothemycin reversible and covalent complexes using docking and extended molecular dynamics simulations. Subsequently, we determined the 2.5A resolution crystal structure of the complex that was in excellent accord with the modeled structure. The results were used to discuss structure-activity relationships, and provide a structural template for the development of irreversible inhibitors that complement the ATP binding site of kinases.


  • Organizational Affiliation

    Dipartimento di Scienze Farmaceutiche, Università di Modena e Reggio Emilia, via Campi 183, 41100 Modena, Italy. giulio.rastelli@unimore.it


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Mitogen-activated protein kinase 1
A, B
357Rattus norvegicusMutation(s): 0 
Gene Names: Erk2
EC: 2.7.11.24
UniProt
Find proteins for P63086 (Rattus norvegicus)
Explore P63086 
Go to UniProtKB:  P63086
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP63086
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
HMY
Query on HMY

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
(1aR,8S,13S,14S,15aR)-5,13,14-trihydroxy-3-methoxy-8-methyl-8,9,13,14,15,15a-hexahydro-6H-oxireno[k][2]benzoxacyclotetradecine-6,12(1aH)-dione
C19 H22 O8
SSNQAUBBJYCSMY-LWQPPDATSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.274 
  • R-Value Work: 0.197 
  • R-Value Observed: 0.201 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 45.815α = 90
b = 117.298β = 89.82
c = 65.871γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2008-07-08
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2017-10-25
    Changes: Refinement description
  • Version 1.3: 2023-11-01
    Changes: Data collection, Database references, Derived calculations, Refinement description