02833nas a2200445   4500000000100000008004100001260001300042653003400055653002500089653003200114653003300146653002000179653002500199653002100224653002800245653002200273653002300295653002300318653002700341653002600368653001800394653002400412653002300436653002600459100001300485700001200498700001700510700001200527700001500539700001300554700001400567700001600581700001100597700001300608245014900621300001300770490000700783520158300790022001402373       2007                            d  c2007 Sep10aSequence Homology, Amino Acid10aS-Adenosylmethionine10aProtein Structure, Tertiary10aProtein Structure, Secondary10aProtein Binding10aMycobacterium leprae10aMycobacteriaceae10aMolecular Sequence Data10aModels, Molecular10aMethyltransferases10aDatabases, Protein10aCrystallography, X-Ray10aComputational Biology10aBinding Sites10aAmino Acid Sequence10aStatic Electricity10aSubstrate Specificity1 aGraña M1 aHaouz A1 aBuschiazzo A1 aMiras I1 aWehenkel A1 aBondet V1 aShepard W1 aSchaeffer F1 aCole S1 aAlzari P00aThe crystal structure of M. leprae ML2640c defines a large family of putative S-adenosylmethionine-dependent methyltransferases in mycobacteria.  a1896-9040 v163 a<p>Mycobacterium leprae protein ML2640c belongs to a large family of conserved hypothetical proteins predominantly found in mycobacteria, some of them predicted as putative S-adenosylmethionine (AdoMet)-dependent methyltransferases (MTase). As part of a Structural Genomics initiative on conserved hypothetical proteins in pathogenic mycobacteria, we have determined the structure of ML2640c in two distinct crystal forms. As expected, ML2640c has a typical MTase core domain and binds the methyl donor substrate AdoMet in a manner consistent with other known members of this structural family. The putative acceptor substrate-binding site of ML2640c is a large internal cavity, mostly lined by aromatic and aliphatic side-chain residues, suggesting that a lipid-like molecule might be targeted for catalysis. A flap segment (residues 222-256), which isolates the binding site from the bulk solvent and is highly mobile in the crystal structures, could serve as a gateway to allow substrate entry and product release. The multiple sequence alignment of ML2640c-like proteins revealed that the central alpha/beta core and the AdoMet-binding site are very well conserved within the family. However, the amino acid positions defining the binding site for the acceptor substrate display a higher variability, suggestive of distinct acceptor substrate specificities. The ML2640c crystal structures offer the first structural glimpses at this important family of mycobacterial proteins and lend strong support to their functional assignment as AdoMet-dependent methyltransferases.</p>  a0961-8368