Abstract
During tRNA maturation tRNAHis guanylyltransferase (Thg1) catalyzes the untemplated 3'-5' addition of a G to the tRNA 5'-end. This additional guanylate provides the major identity element for histidyl-tRNA synthetase to recognize its cognate tRNAHis. Thg1 is a structural homolog of canonical 5'-3' polymerases. Here, we report the structures of Candida albicans Thg1 with its substrates tRNA, or ATP, or GTP. Two tRNAs bind to the tetrameric enzyme complex, but interaction of three subunits is required for tRNA positioning and catalytic activity. The tRNA substrate enters the Thg1 active site from the opposite direction compared to canonical 5'-3' polymerases, indicating that the directionality of nucleotide polymerization is strongly related to the directionality of substrate access. Structural and biochemical data support a reaction model of Thg1 that catalyzes reverse nucleotide addition.
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