ArticleNature communications2024
3D variability analysis reveals a hidden conformational change controlling ammonia transport in human asparagine synthetase.
Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- Human TBC1 domain-containing kinase is a class I multidomain pseudokinase.Protein expression and purification · 2027Article
- Glutamine metabolic enzymes: to filament or not to filament?Biochemical Society transactions · 2026Review
- A Foundational Shift in Models for Enzyme Function.Journal of the American Chemical Society · 2025Review
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10 authors.
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Abstract
Advances in X-ray crystallography and cryogenic electron microscopy (cryo-EM) offer the promise of elucidating functionally relevant conformational changes that are not easily studied by other biophysical methods. Here we show that 3D variability analysis (3DVA) of the cryo-EM map for wild-type (WT) human asparagine synthetase (ASNS) identifies a functional role for the Arg-142 side chain and test this hypothesis experimentally by characterizing the R142I variant in which Arg-142 is replaced by isoleucine. Support for Arg-142 playing a role in the intramolecular translocation of ammonia between the active site of the enzyme is provided by the glutamine-dependent synthetase activity of the R142 variant relative to WT ASNS, and MD simulations provide a possible molecular mechanism for these findings. Combining 3DVA with MD simulations is a generally applicable approach to generate testable hypotheses of how conformational changes in buried side chains might regulate function in enzymes.
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