SNAP output for PDB entry 6px3 [SNAP web server]

PDB-id

6px3; SNAP-derived features in text and JSON formats; DNAproDB

Class

gene regulation

Method

cryo-EM (4.1 Å)

Summary

Set2 bound to nucleosome

Reference

Bilokapic S, Halic M (2019): "Nucleosome and ubiquitin position Set2 to methylate H3K36." Nat Commun, 10, 3795. doi: 10.1038/s41467-019-11726-4.

Abstract

Histone H3 lysine 36 methylation (H3K36me) is a conserved histone modification deposited by the Set2 methyltransferases. Recent findings show that over-expression or mutation of Set2 enzymes promotes cancer progression, however, mechanisms of H3K36me are poorly understood. Set2 enzymes show spurious activity on histones and histone tails, and it is unknown how they obtain specificity to methylate H3K36 on the nucleosome. In this study, we present 3.8 Å cryo-EM structure of Set2 bound to the mimic of H2B ubiquitinated nucleosome. Our structure shows that Set2 makes extensive interactions with the H3 αN, the H3 tail, the H2A C-terminal tail and stabilizes DNA in the unwrapped conformation, which positions Set2 to specifically methylate H3K36. Moreover, we show that ubiquitin contributes to Set2 positioning on the nucleosome and stimulates the methyltransferase activity. Notably, our structure uncovers interfaces that can be targeted by small molecules for development of future cancer therapies.