title: Characterization of the cofactor-binding site in the SPOUT-fold methyltransferases by computational docking of S-adenosylmethionine to three crystal structures.
abstract: BACKGROUND
  There are several evolutionarily unrelated and structurally dissimilar superfamilies of S-adenosylmethionine (AdoMet)-dependent methyltransferases (MTases). A new superfamily (SPOUT) has been recently characterized on a sequence level and three structures of its members (1gz0, 1ipa, and 1k3r) have been solved. However, none of these structures include the cofactor or the substrate. Due to the strong evolutionary divergence and the paucity of experimental information, no confident predictions of protein-ligand and protein-substrate interactions could be made, which hampered the study of sequence-structure-function relationships in the SPOUT superfamily.
  
  
  RESULTS
  We used the computational docking program AutoDock to identify the AdoMet-binding site on the surface of three MTase structures. We analyzed the sequence divergence in two distinct lineages of the SPOUT superfamily in the context of surface features and preferred cofactor binding mode to propose specific function for the conserved residues.
  
  
  CONCLUSIONS
  Our docking analysis has confidently predicted the common AdoMet-binding site in three remotely related proteins structures. In the vicinity of the cofactor-binding site, subfamily-conserved grooves were identified on the protein surface, suggesting location of the target-binding/catalytic site. Functionally important residues were inferred and a general reaction mechanism, involving conformational change of a glycine-rich loop, was proposed.
authors.affiliation: Bioinformatics Laboratory, International Institute of Molecular and Cell Biology, Trojdena 4, 02-109 Warsaw, Poland. michal@genesilico.pl
authors.forename: Michal A
authors.initials: MA
authors.lastname: Kurowski
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Sasin
authors.forename: Marcin
authors.initials: M
authors.lastname: Feder
authors.forename: Janusz
authors.initials: J
authors.lastname: Debski
authors.forename: Janusz M
authors.initials: JM
authors.lastname: Bujnicki
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D003067:Coenzymes / Q000737:chemistry*; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D018360:Crystallography, X-Ray / Q000379:methods*; D011487:Protein Conformation; D017510:Protein Folding; D012436:S-Adenosylmethionine / Q000737:chemistry*; D013329:Structure-Activity Relationship; D012359:tRNA Methyltransferases / Q000737:chemistry*
chemical_list: D003067:Coenzymes; D012436:S-Adenosylmethionine; D012359:tRNA Methyltransferases