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Dominant mutations in the ubiquitous enzyme glycyl-tRNA synthetase (GlyRS), including S581L, lead to motor nerve degeneration. We have determined crystal structures of wildtype and S581L-mutant human GlyRS. The S581L mutation is approximately 50A from the active site, and yet gives reduced aminoacylation activity. The overall structures of wildtype and S581L-GlyRS, including the active site, are very similar. However, residues 567-575 of the anticodon-binding domain shift position and in turn could indirectly affect glycine binding via the tRNA or alternatively inhibit conformational changes. Reduced enzyme activity may underlie neuronal degeneration, although a dominant-negative effect is more likely in this autosomal dominant disorder.

Original publication




Journal article



Publication Date





2959 - 2964


Amino Acid Substitution, Binding Sites, Crystallography, X-Ray, Dimerization, Distal Myopathies, Glycine-tRNA Ligase, Humans, Leucine, Models, Molecular, Muscular Atrophy, Spinal, Mutant Proteins, Mutation, Missense, RNA-Binding Proteins, Serine, Transfer RNA Aminoacylation