7OS4

Crystal structure of mouse CARM1 in complex with histone H3_13-31 K18


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.54 Å
  • R-Value Free: 0.255 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.210 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structural Studies Provide New Insights into the Role of Lysine Acetylation on Substrate Recognition by CARM1 and Inform the Design of Potent Peptidomimetic Inhibitors.

Zhang, Y.Marechal, N.van Haren, M.J.Troffer-Charlier, N.Cura, V.Cavarelli, J.Martin, N.I.

(2021) Chembiochem 22: 3469-3476

  • DOI: https://doi.org/10.1002/cbic.202100506
  • Primary Citation of Related Structures:  
    7OKP, 7OS4

  • PubMed Abstract: 

    The dynamic interplay of post-translational modifications (PTMs) in chromatin provides a communication system for the regulation of gene expression. An increasing number of studies have highlighted the role that such crosstalk between PTMs plays in chromatin recognition. In this study, (bio)chemical and structural approaches were applied to specifically probe the impact of acetylation of Lys 18 in the histone H3 tail peptide on peptide recognition by the protein methyltransferase coactivator-associated arginine methyltransferase 1 (CARM1). Peptidomimetics that recapitulate the transition state of protein arginine N-methyltransferases, were designed based on the H3 peptide wherein the target Arg 17 was flanked by either a free or an acetylated lysine. Structural studies with these peptidomimetics and the catalytic domain of CARM1 provide new insights into the binding of the H3 peptide within the enzyme active site. While the co-crystal structures reveal that lysine acetylation results in minor conformational differences for both CARM1 and the H3 peptide, acetylation of Lys 18 does lead to additional interactions (Van der Waals and hydrogen bonding) and likely reduces the cost of desolvation upon binding, resulting in increased affinity. Informed by these findings a series of smaller peptidomimetics were also prepared and found to maintain potent and selective CARM1 inhibition. These findings provide new insights both into the mechanism of crosstalk between arginine methylation and lysine acetylation as well as towards the development of peptidomimetic CARM1 inhibitors.


  • Organizational Affiliation

    Biological Chemistry Group, Institute of Biology Leiden, Leiden University, Sylviusweg 72, 2333 BE, Leiden (The, Netherlands.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Histone-arginine methyltransferase CARM1
A, B, C, D
371Mus musculusMutation(s): 0 
Gene Names: Carm1Prmt4
EC: 2.1.1.319
UniProt & NIH Common Fund Data Resources
Find proteins for Q9WVG6 (Mus musculus)
Explore Q9WVG6 
Go to UniProtKB:  Q9WVG6
IMPC:  MGI:1913208
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9WVG6
Sequence Annotations
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  • Reference Sequence

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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Histone H3.1
E, F, G, H
20Mus musculusMutation(s): 1 
UniProt
Find proteins for P68433 (Mus musculus)
Explore P68433 
Go to UniProtKB:  P68433
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP68433
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.54 Å
  • R-Value Free: 0.255 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.210 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 74.374α = 90
b = 98.606β = 90
c = 206.61γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
XDSdata 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: 2021-10-27
    Type: Initial release
  • Version 1.1: 2021-12-22
    Changes: Database references
  • Version 1.2: 2024-01-31
    Changes: Data collection, Refinement description