3HY0

Crystal Structure of catalytic fragment of E. coli AlaRS G237A in complex with GlySA

Summary for 3HY0

• Entry DOI: 10.2210/pdb3hy0/pdb
• Related: 3HXU 3HXV 3HXW 3HXX 3HXY 3HXZ 3HY1
• Descriptor: Alanyl-tRNA synthetase, 5'-O-(glycylsulfamoyl)adenosine, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID, ... (5 entities in total)
• Functional Keywords: aminoacyl-trna synthetase, ligase, protein biosynthesis, nucleotide-binding, amino acid-binding, atp-binding, metal-binding, zinc-finger
• Biological source: Escherichia coli
• Cellular location: Cytoplasm: P00957
• Total number of polymer chains: 2
• Total formula weight: 101776.52

Authors

Guo, M.,Yang, X.-L.,Schimmel, P. (deposition date: 2009-06-22, release date: 2009-12-15, Last modification date: 2024-02-21)

Primary citation

Guo, M.,Chong, Y.E.,Shapiro, R.,Beebe, K.,Yang, X.L.,Schimmel, P.
Paradox of mistranslation of serine for alanine caused by AlaRS recognition dilemma.
Nature, 462:808-812, 2009

PubMed 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.

PubMed: 20010690
DOI: 10.1038/nature08612

Experimental method

X-RAY DIFFRACTION (1.9 Å)