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PDBsum entry 3hxx
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References listed in PDB file
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Key reference
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Title
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Paradox of mistranslation of serine for alanine caused by alars recognition dilemma.
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Authors
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M.Guo,
Y.E.Chong,
R.Shapiro,
K.Beebe,
X.L.Yang,
P.Schimmel.
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Ref.
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Nature, 2009,
462,
808-812.
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PubMed id
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Abstract
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Mistranslation arising from confusion of serine for alanine by alanyl-tRNA
synthetases (AlaRSs) has profound functional consequences. Throughout evolution,
two editing checkpoints prevent disease-causing mistranslation from confusing
glycine or serine for alanine at the active site of AlaRS. In both bacteria and
mice, Ser poses a bigger challenge than Gly. One checkpoint is the AlaRS editing
centre, and the other is from widely distributed AlaXps-free-standing,
genome-encoded editing proteins that clear Ser-tRNA(Ala). The paradox of
misincorporating both a smaller (glycine) and a larger (serine) amino acid
suggests a deep conflict for nature-designed AlaRS. Here we show the chemical
basis for this conflict. Nine crystal structures, together with kinetic and
mutational analysis, provided snapshots of adenylate formation for each amino
acid. An inherent dilemma is posed by constraints of a structural design that
pins down the alpha-amino group of the bound amino acid by using an acidic
residue. This design, dating back more than 3 billion years, creates a
serendipitous interaction with the serine OH that is difficult to avoid.
Apparently because no better architecture for the recognition of alanine could
be found, the serine misactivation problem was solved through free-standing
AlaXps, which appeared contemporaneously with early AlaRSs. The results reveal
unconventional problems and solutions arising from the historical design of the
protein synthesis machinery.
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