title: Structure and catalytic mechanism of a SET domain protein methyltransferase.
abstract: Protein lysine methylation by SET domain enzymes regulates chromatin structure, gene silencing, transcriptional activation, plant metabolism, and other processes. The 2.6 A resolution structure of Rubisco large subunit methyltransferase in a pseudo-bisubstrate complex with S-adenosylhomocysteine and a HEPES ion reveals an all-beta architecture for the SET domain embedded within a larger alpha-helical enzyme fold. Conserved regions of the SET domain bind S-adenosylmethionine and substrate lysine at two sites connected by a pore. We propose that methyl transfer is catalyzed by a conserved Tyr at a narrow pore connecting the sites. The cofactor enters by a "back door" on the opposite side of the enzyme from substrate, promoting highly specific protein recognition and allowing addition of multiple methyl groups.
authors.affiliation: Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Trievel
authors.forename: Bridgette M
authors.initials: BM
authors.lastname: Beach
authors.forename: Lynnette M A
authors.initials: LM
authors.lastname: Dirk
authors.forename: Robert L
authors.initials: RL
authors.lastname: Houtz
authors.forename: James H
authors.initials: JH
authors.lastname: Hurley
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001665:Binding Sites; D002843:Chromatin / Q000737:chemistry; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000737:chemistry*; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D029721:Drosophila Proteins / Q000737:chemistry*; D004583:Electrons; D020868:Gene Silencing; D006531:HEPES / Q000494:pharmacology; D006657:Histones / Q000737:chemistry; D007700:Kinetics; D008024:Ligands; D008239:Lysine / Q000737:chemistry; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry*; D018532:Pisum sativum / Q000201:enzymology; D063151:Polycomb Repressive Complex 2; D011485:Protein Binding; D011496:Protein Methyltransferases / Q000737:chemistry*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000737:chemistry*; D018724:Spinacia oleracea / Q000201:enzymology; D013379:Substrate Specificity; D014157:Transcription Factors; D015533:Transcriptional Activation; D014443:Tyrosine / Q000737:chemistry
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D006657:Histones; D008024:Ligands; D009687:Nuclear Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C063460:Trl protein, Drosophila; D014443:Tyrosine; D011496:Protein Methyltransferases; C083329:E(z) protein, Drosophila; D063151:Polycomb Repressive Complex 2; D008239:Lysine; D006531:HEPES