Allostery can convert binding free energies into concerted domain motions in enzymes

Nicole Stéphanie Galenkamp, Sarah Zernia, Yulan B Van Oppen, Marco van den Noort, Andreas Milias Argeitis, Giovanni Maglia*

*Corresponding author voor dit werk

OnderzoeksoutputAcademicpeer review

1 Citaat (Scopus)
2 Downloads (Pure)

Samenvatting

Enzymatic mechanisms are typically inferred from structural data. However, understanding enzymes require unravelling the intricate dynamic interplay between dynamics, conformational substates, and multiple protein structures. Here, we use single-molecule nanopore analysis to investigate the catalytic conformational changes of adenylate kinase (AK), an enzyme that catalyzes the interconversion of various adenosine phosphates (ATP, ADP, and AMP). Kinetic analysis validated by hidden Markov models unravels the details of domain motions during catalysis. Our findings reveal that allosteric interactions between ligands and cofactor enable converting binding energies into directional conformational changes of the two catalytic domains of AK. These coordinated motions emerged to control the exact sequence of ligand binding and the affinity for the three different substrates, thereby guiding the reactants along the reaction coordinates. Interestingly, we find that about 10% of enzymes show altered allosteric regulation and ligand affinities, indicating that a subset of enzymes folds in alternative catalytically active forms. Since molecules or proteins might be able to selectively stabilize one of the folds, this observation suggests an evolutionary path for allostery in enzymes. In AK, this complex catalytic framework has likely emerged to prevent futile ATP/ADP hydrolysis and to regulate the enzyme for different energy needs of the cell.

Originele taal-2English
Artikelnummer10109
Aantal pagina's13
TijdschriftNature Communications
Volume15
Nummer van het tijdschrift1
DOI's
StatusPublished - 22-nov.-2024

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