Differentiating Analogous Trna Methyltransferases by Fragments of the Methyl Donor
Downloaded from rnajournal.cshlp.org on September 23, 2021 - Published by Cold Spring Harbor Laboratory Press Differentiating analogous tRNA methyltransferases by fragments of the methyl donor GEORGES LAHOUD,1 SAKURAKO GOTO-ITO,2,3 KEN-ICHI YOSHIDA,2,3 TAKUHIRO ITO,2 SHIGEYUKI YOKOYAMA,2,3 and YA-MING HOU1,4 1Thomas Jefferson University, Department of Biochemistry and Molecular Biology, Philadelphia, Pennsylvania 19107, USA 2RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro, Tsurumi, Yokohama, Kanagawa 230-0045, Japan 3Department of Biophysics and Biochemistry, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan ABSTRACT Bacterial TrmD and eukaryotic-archaeal Trm5 form a pair of analogous tRNA methyltransferase that catalyze methyl transfer from S-adenosyl methionine (AdoMet) to N1 of G37, using catalytic motifs that share no sequence or structural homology. Here we show that natural and synthetic analogs of AdoMet are unable to distinguish TrmD from Trm5. Instead, fragments of AdoMet, adenosine and methionine, are selectively inhibitory of TrmD rather than Trm5. Detailed structural information of the two enzymes in complex with adenosine reveals how Trm5 escapes targeting by adopting an altered structure, whereas TrmD is trapped by targeting due to its rigid structure that stably accommodates the fragment. Free energy analysis exposes energetic disparities between the two enzymes in how they approach the binding of AdoMet versus fragments and provides insights into the design of inhibitors selective for TrmD. Keywords: S-adenosyl methionine (AdoMet); adenosine; methionine; m1G37-tRNA INTRODUCTION veloped and adapted over time with comparable substrate binding affinities. This presents severe challenges to the con- Analogous enzymes are thought to be independent inven- ventional approach of structure-based design of substrate tions of nature (Galperin et al.
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