3SA0

Complex of ERK2 with norathyriol


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.59 Å
  • R-Value Free: 0.200 
  • R-Value Work: 0.164 
  • R-Value Observed: 0.166 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Norathyriol Suppresses Skin Cancers Induced by Solar Ultraviolet Radiation by Targeting ERK Kinases.

Li, J.Malakhova, M.Mottamal, M.Reddy, K.Kurinov, I.Carper, A.Langfald, A.Oi, N.Kim, M.O.Zhu, F.Sosa, C.P.Zhou, K.Bode, A.M.Dong, Z.

(2012) Cancer Res 72: 260-270

  • DOI: https://doi.org/10.1158/0008-5472.CAN-11-2596
  • Primary Citation of Related Structures:  
    3SA0

  • PubMed Abstract: 

    Ultraviolet (UV) irradiation is the leading factor in the development of skin cancer, prompting great interest in chemopreventive agents for this disease. In this study, we report the discovery of norathyriol, a plant-derived chemopreventive compound identified through an in silico virtual screening of the Chinese Medicine Library. Norathyriol is a metabolite of mangiferin found in mango, Hypericum elegans, and Tripterospermum lanceolatum and is known to have anticancer activity. Mechanistic investigations determined that norathyriol acted as an inhibitor of extracellular signal-regulated kinase (ERK)1/2 activity to attenuate UVB-induced phosphorylation in mitogen-activated protein kinases signaling cascades. We confirmed the direct and specific binding of norathyriol with ERK2 through a cocrystal structural analysis. The xanthone moiety in norathyriol acted as an adenine mimetic to anchor the compound by hydrogen bonds to the hinge region of the protein ATP-binding site on ERK2. Norathyriol inhibited in vitro cell growth in mouse skin epidermal JB6 P+ cells at the level of G(2)-M phase arrest. In mouse skin tumorigenesis assays, norathyriol significantly suppressed solar UV-induced skin carcinogenesis. Further analysis indicated that norathyriol mediates its chemopreventive activity by inhibiting the ERK-dependent activity of transcriptional factors AP-1 and NF-κB during UV-induced skin carcinogenesis. Taken together, our results identify norathyriol as a safe new chemopreventive agent that is highly effective against development of UV-induced skin cancer.


  • Organizational Affiliation

    The Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Mitogen-activated protein kinase 1360Homo sapiensMutation(s): 0 
Gene Names: ERK2MAPK1PRKM1PRKM2
EC: 2.7.11.24
UniProt & NIH Common Fund Data Resources
Find proteins for P28482 (Homo sapiens)
Explore P28482 
Go to UniProtKB:  P28482
PHAROS:  P28482
GTEx:  ENSG00000100030 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP28482
Sequence Annotations
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  • Reference Sequence
Small Molecules
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
CME
Query on CME
A
L-PEPTIDE LINKINGC5 H11 N O3 S2CYS
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.59 Å
  • R-Value Free: 0.200 
  • R-Value Work: 0.164 
  • R-Value Observed: 0.166 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 48.687α = 90
b = 69.411β = 108.99
c = 59.721γ = 90
Software Package:
Software NamePurpose
ADSCdata collection
PHENIXmodel building
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling
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: 2011-12-14
    Type: Initial release
  • Version 1.1: 2012-01-18
    Changes: Database references
  • Version 1.2: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description