3F9Z

Structural Insights into Lysine Multiple Methylation by SET Domain Methyltransferases, SET8-Y245F / H4-Lys20 / AdoHcy

Summary for 3F9Z

• Entry DOI: 10.2210/pdb3f9z/pdb
• Related: 1ZKK 3F9W 3F9X 3F9Y
• Descriptor: Histone-lysine N-methyltransferase SETD8, Histone H4, S-ADENOSYL-L-HOMOCYSTEINE, ... (4 entities in total)
• Functional Keywords: methyltransferase, histone, set, lysine, alternative splicing, cell cycle, cell division, chromatin regulator, chromosomal protein, coiled coil, mitosis, nucleus, repressor, s-adenosyl-l-methionine, transcription, transcription regulation, acetylation, dna-binding, methylation, nucleosome core, transferase
• Biological source: Homo sapiens; More
• Cellular location: Nucleus: Q9NQR1 P62805
• Total number of polymer chains: 8
• Total formula weight: 81772.90

Authors

Couture, J.-F.,Dirk, L.M.A.,Brunzelle, J.S.,Houtz, R.L.,Trievel, R.C. (deposition date: 2008-11-14, release date: 2008-11-25, Last modification date: 2023-09-06)

Primary citation

Couture, J.F.,Dirk, L.M.,Brunzelle, J.S.,Houtz, R.L.,Trievel, R.C.
Structural origins for the product specificity of SET domain protein methyltransferases.
Proc.Natl.Acad.Sci.Usa, 105:20659-20664, 2008

PubMed Abstract: SET domain protein lysine methyltransferases (PKMTs) regulate transcription and other cellular functions through site-specific methylation of histones and other substrates. PKMTs catalyze the formation of monomethylated, dimethylated, or trimethylated products, establishing an additional hierarchy with respect to methyllysine recognition in signaling. Biochemical studies of PKMTs have identified a conserved position within their active sites, the Phe/Tyr switch, that governs their respective product specificities. To elucidate the mechanism underlying this switch, we have characterized a Phe/Tyr switch mutant of the histone H4 Lys-20 (H4K20) methyltransferase SET8, which alters its specificity from a monomethyltransferase to a dimethyltransferase. The crystal structures of the SET8 Y334F mutant bound to histone H4 peptides bearing unmodified, monomethyl, and dimethyl Lys-20 reveal that the phenylalanine substitution attenuates hydrogen bonding to a structurally conserved water molecule adjacent to the Phe/Tyr switch, facilitating its dissociation. The additional space generated by the solvent's dissociation enables the monomethyllysyl side chain to adopt a conformation that is catalytically competent for dimethylation and furnishes sufficient volume to accommodate the dimethyl epsilon-ammonium product. Collectively, these results indicate that the Phe/Tyr switch regulates product specificity through altering the affinity of an active-site water molecule whose dissociation is required for lysine multiple methylation.

PubMed: 19088188
DOI: 10.1073/pnas.0806712105

Experimental method

X-RAY DIFFRACTION (1.6 Å)