title: Dynamically committed, uncommitted, and quenched states encoded in protein kinase A revealed by NMR spectroscopy.
abstract: Protein kinase A (PKA) is a ubiquitous phosphoryl transferase that mediates hundreds of cell signaling events. During turnover, its catalytic subunit (PKA-C) interconverts between three major conformational states (open, intermediate, and closed) that are dynamically and allosterically activated by nucleotide binding. We show that the structural transitions between these conformational states are minimal and allosteric dynamics encode the motions from one state to the next. NMR and molecular dynamics simulations define the energy landscape of PKA-C, with the substrate allowing the enzyme to adopt a broad distribution of conformations (dynamically committed state) and the inhibitors (high magnesium and pseudosubstrate) locking it into discrete minima (dynamically quenched state), thereby reducing the motions that allow turnover. These results unveil the role of internal dynamics in both kinase function and regulation.
authors.affiliation: Department of Biochemistry, University of Minnesota, Minneapolis, MN 55455-0431, USA.
authors.forename: Larry R
authors.initials: LR
authors.lastname: Masterson
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.forename: Emily
authors.initials: E
authors.lastname: Metcalfe
authors.forename: Jiali
authors.initials: J
authors.lastname: Gao
authors.forename: Susan S
authors.initials: SS
authors.lastname: Taylor
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Veglia
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D020134:Catalytic Domain; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D013329:Structure-Activity Relationship
chemical_list: D017868:Cyclic AMP-Dependent Protein Kinases