title: Structural and functional profiling of the human histone methyltransferase SMYD3.
abstract: The SET and MYND Domain (SMYD) proteins comprise a unique family of multi-domain SET histone methyltransferases that are implicated in human cancer progression. Here we report an analysis of the crystal structure of the full length human SMYD3 in a complex with an analog of the S-adenosyl methionine (SAM) methyl donor cofactor. The structure revealed an overall compact architecture in which the "split-SET" domain adopts a canonical SET domain fold and closely assembles with a Zn-binding MYND domain and a C-terminal superhelical 9 α-helical bundle similar to that observed for the mouse SMYD1 structure. Together, these structurally interlocked domains impose a highly confined binding pocket for histone substrates, suggesting a regulated mechanism for its enzymatic activity. Our mutational and biochemical analyses confirm regulatory roles of the unique structural elements both inside and outside the core SET domain and establish a previously undetected preference for trimethylation of H4K20.
authors.affiliation: OSI Pharmaceuticals, Inc., Farmingdale, New York, United States of America. kforeman@coferon.com
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Foreman
authors.forename: Mark
authors.initials: M
authors.lastname: Brown
authors.forename: Frances
authors.initials: F
authors.lastname: Park
authors.forename: Spencer
authors.initials: S
authors.lastname: Emtage
authors.forename: June
authors.initials: J
authors.lastname: Harriss
authors.forename: Chhaya
authors.initials: C
authors.lastname: Das
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.forename: Andy
authors.initials: A
authors.lastname: Crew
authors.forename: Lee
authors.initials: L
authors.lastname: Arnold
authors.forename: Salam
authors.initials: S
authors.lastname: Shaaban
authors.forename: Philip
authors.initials: P
authors.lastname: Tucker
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism; D001665:Binding Sites; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry* / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D011485:Protein Binding; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship
chemical_list: D006657:Histones; D011495:Histone-Lysine N-Methyltransferase; C506278:SMYD3 protein, human; D000241:Adenosine; C006235:sinefungin