Globally correlated conformational entropy underlies positive and negative cooperativity in a kinase’s enzymatic cycle

Yingjie Wang, Manu V.S., Jonggul Kim, Geoffrey Li, Lalima G. Ahuja, Philip Aoto, Susan S. Taylor and Gianluigi Veglia ()
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Yingjie Wang: University of Minnesota
Manu V.S.: University of Minnesota
Jonggul Kim: University of Minnesota
Geoffrey Li: University of Minnesota
Lalima G. Ahuja: and Pharmacology University of California at San Diego
Philip Aoto: and Pharmacology University of California at San Diego
Susan S. Taylor: and Pharmacology University of California at San Diego
Gianluigi Veglia: University of Minnesota

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: Abstract Enzymes accelerate the rate of chemical transformations by reducing the activation barriers of uncatalyzed reactions. For signaling enzymes, substrate recognition, binding, and product release are often rate-determining steps in which enthalpy-entropy compensation plays a crucial role. While the nature of enthalpic interactions can be inferred from structural data, the molecular origin and role of entropy in enzyme catalysis remains poorly understood. Using thermocalorimetry, NMR, and MD simulations, we studied the conformational landscape of the catalytic subunit of cAMP-dependent protein kinase A, a ubiquitous phosphoryl transferase involved in a myriad of cellular processes. Along the enzymatic cycle, the kinase exhibits positive and negative cooperativity for substrate and nucleotide binding and product release. We found that globally coordinated changes of conformational entropy activated by ligand binding, together with synchronous and asynchronous breathing motions of the enzyme, underlie allosteric cooperativity along the kinase’s cycle.

Date: 2019
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DOI: 10.1038/s41467-019-08655-7

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