3PSL

Fine-tuning the stimulation of MLL1 methyltransferase activity by a histone H3 based peptide mimetic

Summary for 3PSL

• Entry DOI: 10.2210/pdb3psl/pdb
• Descriptor: WD repeat-containing protein 5, N-alpha acetylated form of histone H3 (3 entities in total)
• Functional Keywords: chromatin, histone, beta-propeller, scaffolding, rbbp5, mll1, nucleus, transcription - transcription inhibitor complex, transcription-transcription inhibitor complex, transcription/transcription inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: P61964
• Total number of polymer chains: 4
• Total formula weight: 70850.37

Authors

Avdic, V.,Zhang, P.,Lanouette, S.,Voronova, A.,Skerjanc, I.,Couture, J.-F. (deposition date: 2010-12-01, release date: 2010-12-22, Last modification date: 2024-11-27)

Primary citation

Avdic, V.,Zhang, P.,Lanouette, S.,Voronova, A.,Skerjanc, I.,Couture, J.F.
Fine-tuning the stimulation of MLL1 methyltransferase activity by a histone H3-based peptide mimetic.
Faseb J., 25:960-967, 2011

PubMed Abstract: The SET1 family of methyltransferases carries out the bulk of histone H3 Lys-4 methylation in vivo. One of the common features of this family is the regulation of their methyltransferase activity by a tripartite complex composed of WDR5, RbBP5, and Ash2L. To selectively probe the role of the SET1 family of methyltransferases, we have developed a library of histone H3 peptide mimetics and report herein the characterization of an Nα acetylated form of histone H3 peptide (NαH3). Binding and inhibition studies reveal that the addition of an acetyl moiety to the N terminus of histone H3 significantly enhances its binding to WDR5 and prevents the stimulation of MLL1 methyltransferase activity by the WDR5-RbBP5-Ash2L complex. The crystal structure of NαH3 in complex with WDR5 reveals that a high-affinity hydrophobic pocket accommodates the binding of the acetyl moiety. These results provide the structural basis to control WDR5-RbBP5-Ash2L-MLL1 activity and a tool to manipulate stem cell differentiation programs.

PubMed: 21135039
DOI: 10.1096/fj.10-171959

Experimental method

X-RAY DIFFRACTION (1.7 Å)