Location of the Y454S substitution in the structure of human HARS. A) The Y454S substitution is located in the anticodon-binding domain juxtaposed to the catalytic domain of the opposing monomer. B) Y454 hydrogen bonds with the conserved E439. C) Modeling the serine at Y454 position in the anticodon- binding domain creates a 6 Å gap between E439 and S454, potentially eliminating a structure-stabilizing hydrogen bonding interaction. D) A portion of the complete sequence alignment (Clustal Omega) of HARS protein sequences from Homo sapiens, Bos taurus, Mus musculus, Danio rerio, Drosophila melanogaster, Caenorhabditis elegans, Trypanosoma bruceii, Saccharomyces cerevisiae, Thermus thermophilus, Staphylococcus aureus and Escherichia coli.