6WK1

SETD3 in Complex with an Actin Peptide with His73 Replaced with Methionine

Summary for 6WK1

• Entry DOI: 10.2210/pdb6wk1/pdb
• Descriptor: Actin, cytoplasmic 2, Actin-histidine N-methyltransferase, GLYCEROL, ... (7 entities in total)
• Functional Keywords: transferase, transferase-structural protein complex
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 144642.24

Authors

Dai, S.,Horton, J.R.,Cheng, X. (deposition date: 2020-04-15, release date: 2020-06-17, Last modification date: 2023-10-18)

Primary citation

Dai, S.,Holt, M.V.,Horton, J.R.,Woodcock, C.B.,Patel, A.,Zhang, X.,Young, N.L.,Wilkinson, A.W.,Cheng, X.
Characterization of SETD3 methyltransferase-mediated protein methionine methylation.
J.Biol.Chem., 295:10901-10910, 2020

PubMed Abstract: Most characterized protein methylation events encompass arginine and lysine -methylation, and only a few cases of protein methionine thiomethylation have been reported. Newly discovered oncohistone mutations include lysine-to-methionine substitutions at positions 27 and 36 of histone H3.3. In these instances, the methionine substitution localizes to the active-site pocket of the corresponding histone lysine methyltransferase, thereby inhibiting the respective transmethylation activity. SET domain-containing 3 (SETD3) is a protein ( actin) histidine methyltransferase. Here, we generated an actin variant in which the histidine target of SETD3 was substituted with methionine. As for previously characterized histone SET domain proteins, the methionine substitution substantially (76-fold) increased binding affinity for SETD3 and inhibited SETD3 activity on histidine. Unexpectedly, SETD3 was active on the substituted methionine, generating -methylmethionine in the context of actin peptide. The ternary structure of SETD3 in complex with the methionine-containing actin peptide at 1.9 Å resolution revealed that the hydrophobic thioether side chain is packed by the aromatic rings of Tyr and Trp, as well as the hydrocarbon side chain of Ile Our results suggest that placing methionine properly in the active site-within close proximity to and in line with the incoming methyl group of SAM-would allow some SET domain proteins to selectively methylate methionine in proteins.

PubMed: 32503840
DOI: 10.1074/jbc.RA120.014072

Experimental method

X-RAY DIFFRACTION (1.89 Å)