Crystal Structures of Trypanosomal Histidyl-tRNA Synthetase Illuminate Differences between Eukaryotic and Prokaryotic Homologs

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• 作者：Ethan A. Merritt ; Tracy L. Arakaki ; J. Robert Gillespie ; Eric T. Larson ; Angela Kelley ; Natascha Mueller ; Alberto J. Napuli ; Jessica Kim ; Li Zhang ; Christophe L.M.J. Verlinde ; Erkang Fan ; Frank Zucker
• 关键词：aminoacyl-tRNA synthetase ; protozoa ; drug target ; tropical disease ; RNAi
• 刊名：Journal of Molecular Biology
• 出版年：2010
• 出版时间：26 March 2010
• 年：2010
• 卷：397
• 期：2
• 页码：481-494
• 全文大小：1896 K

文摘

Crystal structures of histidyl-tRNA synthetase (HisRS) from the eukaryotic parasites Trypanosoma brucei and Trypanosoma cruzi provide a first structural view of a eukaryotic form of this enzyme and reveal differences from bacterial homologs. HisRSs in general contain an extra domain inserted between conserved motifs 2 and 3 of the Class II aminoacyl-tRNA synthetase catalytic core. The current structures show that the three-dimensional topology of this domain is very different in bacterial and archaeal/eukaryotic forms of the enzyme. Comparison of apo and histidine-bound trypanosomal structures indicates substantial active-site rearrangement upon histidine binding but relatively little subsequent rearrangement after reaction of histidine with ATP to form the enzyme's first reaction product, histidyladenylate. The specific residues involved in forming the binding pocket for the adenine moiety differ substantially both from the previously characterized binding site in bacterial structures and from the homologous residues in human HisRSs. The essentiality of the single HisRS gene in T. brucei is shown by a severe depression of parasite growth rate that results from even partial suppression of expression by RNA interference.