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Nam K, Thodika ARA, Tischlik S, Phoeurk C, Nagy TM, Schierholz L, Ådén J, Rogne P, Drescher M, Sauer-Eriksson AE, Wolf-Watz M
Sci Adv 10 (32) eado5504 [2024-08-09; online 2024-08-09]
Phosphoryl transfer is a fundamental reaction in cellular signaling and metabolism that requires Mg2+ as an essential cofactor. While the primary function of Mg2+ is electrostatic activation of substrates, such as ATP, the full spectrum of catalytic mechanisms exerted by Mg2+ is not known. In this study, we integrate structural biology methods, molecular dynamic (MD) simulations, phylogeny, and enzymology assays to provide molecular insights into Mg2+-dependent structural reorganization in the active site of the metabolic enzyme adenylate kinase. Our results demonstrate that Mg2+ induces a conformational rearrangement of the substrates (ATP and ADP), resulting in a 30° adjustment of the angle essential for reversible phosphoryl transfer, thereby optimizing it for catalysis. MD simulations revealed transitions between conformational substates that link the fluctuation of the angle to large-scale enzyme dynamics. The findings contribute detailed insight into Mg2+ activation of enzymes and may be relevant for reversible and irreversible phosphoryl transfer reactions.
Swedish NMR Centre (SNC) [Service]
PubMed 39121211
DOI 10.1126/sciadv.ado5504
Crossref 10.1126/sciadv.ado5504