3HY1: Crystal Structure of catalytic fragment of E. coli AlaRS G237A in complex with SerSA

Citation:
Abstract
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.
PDB ID: 3HY1Download
MMDB ID: 78751
PDB Deposition Date: 2009/6/22
Updated in MMDB: 2009/12
Experimental Method:
x-ray diffraction
Resolution: 2.79  Å
Source Organism:
Similar Structures:
Biological Unit for 3HY1: monomeric; determined by author and by software (PISA)
Molecular Components in 3HY1
Label Count Molecule
Protein (1 molecule)
1
Alanyl-trna Synthetase(Gene symbol: alaS)
Molecule annotation
Chemicals (4 molecules)
1
1
2
1
3
1
4
1
* Click molecule labels to explore molecular sequence information.

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