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Magnesium induced structural reorganization in the active site of adenylate kinase.

ABSTRACT: 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.

SUBMITTER: Nam K

PROVIDER: S-EPMC11313852 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Magnesium induced structural reorganization in the active site of adenylate kinase.

Nam Kwangho K Thodika Abdul Raafik Arattu ARA Tischlik Sonja S Phoeurk Chanrith C Nagy Tamás Milán TM Schierholz Léon L Ådén Jörgen J Rogne Per P Drescher Malte M Sauer-Eriksson A Elisabeth AE Wolf-Watz Magnus M

Science advances 20240809 32

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+- ...[more]

PMID: 39121211

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Project description:Many enzymes catalyze reactions with multiple chemical steps, requiring the stabilization of multiple transition states during catalysis. Such enzymes must strike a balance between the conformational reorganization required to stabilize multiple transition states of a reaction and the confines of a preorganized active site in the polypeptide tertiary structure. Here we investigate the compromise between structural reorganization during the catalytic process and preorganization of the active site for a multistep enzyme-catalyzed reaction, the hydrolysis of esters by the Ser-His-Asp/Glu catalytic triad. Quantum mechanical transition states were used to generate ensembles of geometries that can catalyze each individual step in the mechanism. These geometries are compared to each other by superpositions of catalytic atoms to find "consensus" geometries that can catalyze all steps with minimal rearrangement. These consensus geometries are found to be excellent matches for the natural active site. Preorganization is therefore found to be the major defining characteristic of the active site, and reorganizational motions often proposed to promote catalysis have been minimized. The variability of enzyme active sites observed by X-ray crystallography was also investigated empirically. A catalog of geometrical parameters relating active site residues to each other and to bound inhibitors was collected from a set of crystal structures. The crystal-structure-derived values were then compared to the ranges found in quantum mechanically optimized structures along the entire reaction coordinate. The empirical ranges are found to encompass the theoretical ranges when thermal fluctuations are taken into account. Therefore, the active sites are preorganized to a geometry that can be objectively and quantitatively defined as minimizing conformational reorganization while maintaining optimal transition state stabilization for every step during catalysis. The results provide a useful guiding principle for de novo design of enzymes with multistep mechanisms.

Dataset Information

Magnesium induced structural reorganization in the active site of adenylate kinase.

Publications

Magnesium induced structural reorganization in the active site of adenylate kinase.

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