Glutamine synthetase (GS) in Escherichia coli is a crucial enzyme in nitrogen metabolism, regulated by a complex interplay of covalent modifications and allosteric interactions, with adenylation by adenylyltransferase (ATase) serving as a key reversible inhibitory mechanism. While it has been suggested that adenylation shifts the rate-limiting step to substrate activation from product (ADP), release by impacting active site geometry, direct structural evidence has been lacking. Utilizing cryo-electron microscopy (cryoEM), we aim to address this issue by capturing the conformational states of GS under apo, transition state, and turnover conditions, both with and without adenylation and to elucidate the structural basis of this inhibition. Furthermore, the goal is to obtain cryoEM structures of the ternary complex comprising GS and ATase in both adenylation and de-adenylation states, providing critical insights into the rules of engagement for ATase/GS to elicit activity regulation. This work will advance the understanding of enzyme regulation via posttranslational modification of loop structures and mechanism alteration.
Bautista et al. (Sun,) studied this question.
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