Magnesium induced structural reorganization in the active site of adenylate kinase
Kwangho Nam, Abdul Raafik Arattu Thodika, Sonja Tischlik, Chanrith Phoeurk, Tamás Milán Nagy, Léon Schierholz, Jörgen Ådén, Per Rogne, Malte Drescher, A.E. Sauer-Eriksson, Magnus Wolf‐Watz
Abstract
Phosphoryl transfer is a fundamental reaction in cellular signaling and metabolism that requires Mg 2+ as an essential cofactor. While the primary function of Mg 2+ is electrostatic activation of substrates, such as ATP, the full spectrum of catalytic mechanisms exerted by Mg 2+ is not known. In this study, we integrate structural biology methods, molecular dynamic (MD) simulations, phylogeny, and enzymology assays to provide molecular insights into Mg 2+ -dependent structural reorganization in the active site of the metabolic enzyme adenylate kinase. Our results demonstrate that Mg 2+ 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 Mg 2+ activation of enzymes and may be relevant for reversible and irreversible phosphoryl transfer reactions.