7W6J

The crystal structure of MLL1 (N3861I/Q3867L/C3882SS)-RBBP5-ASH2L in complex with H3K4me2 peptide

Summary for 7W6J

• Entry DOI: 10.2210/pdb7w6j/pdb
• Descriptor: Set1/Ash2 histone methyltransferase complex subunit ASH2, Histone-lysine N-methyltransferase 2A, Retinoblastoma-binding protein 5, ... (7 entities in total)
• Functional Keywords: mll family methyltransferases, product specificity, f/y switch, protein binding
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 43707.00

Authors

Zhao, L.,Li, Y.,Chen, Y. (deposition date: 2021-12-01, release date: 2022-09-07, Last modification date: 2023-11-29)

Primary citation

Li, Y.,Zhao, L.,Zhang, Y.,Wu, P.,Xu, Y.,Mencius, J.,Zheng, Y.,Wang, X.,Xu, W.,Huang, N.,Ye, X.,Lei, M.,Shi, P.,Tian, C.,Peng, C.,Li, G.,Liu, Z.,Quan, S.,Chen, Y.
Structural basis for product specificities of MLL family methyltransferases.
Mol.Cell, 82:3810-3825.e8, 2022

PubMed Abstract: Human mixed-lineage leukemia (MLL) family methyltransferases methylate histone H3 lysine 4 to different methylation states (me1/me2/me3) with distinct functional outputs, but the mechanism underlying the different product specificities of MLL proteins remains unclear. Here, we develop methodologies to quantitatively measure the methylation rate difference between mono-, di-, and tri-methylation steps and demonstrate that MLL proteins possess distinct product specificities in the context of the minimum MLL-RBBP5-ASH2L complex. Comparative structural analyses of MLL complexes by X-ray crystal structures, fluorine-19 nuclear magnetic resonance, and molecular dynamics simulations reveal that the dynamics of two conserved tyrosine residues at the "F/Y (phenylalanine/tyrosine) switch" positions fine-tune the product specificity. The variation in the intramolecular interaction between SET-N and SET-C affects the F/Y switch dynamics, thus determining the product specificities of MLL proteins. These results indicate a modified F/Y switch rule applicable for most SET domain methyltransferases and implicate the functional divergence of MLL proteins.

PubMed: 36108631
DOI: 10.1016/j.molcel.2022.08.022

Experimental method

X-RAY DIFFRACTION (2.68 Å)