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Dynamically committed, uncommitted, and quenched states encoded in protein kinase A revealed by NMR spectroscopy.

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... Full description

Journal Title: Proceedings of the National Academy of Sciences of the United States of America April 26, 2011, Vol.108(17), pp.6969-6974
Main Author: Masterson, Larry R
Other Authors: Shi, Lei , Metcalfe, Emily , Gao, Jiali , Taylor, Susan S , Veglia, Gianluigi
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1102701108
Link: http://search.proquest.com/docview/863898444/?pq-origsite=primo
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title: Dynamically committed, uncommitted, and quenched states encoded in protein kinase A revealed by NMR spectroscopy.
format: Article
creator:
  • Masterson, Larry R
  • Shi, Lei
  • Metcalfe, Emily
  • Gao, Jiali
  • Taylor, Susan S
  • Veglia, Gianluigi
subjects:
  • Allosteric Regulation–Chemistry
  • Animals–Genetics
  • Catalytic Domain–Metabolism
  • Cyclic Amp-Dependent Protein Kinases–Metabolism
  • Humans–Metabolism
  • Models, Molecular–Metabolism
  • Nuclear Magnetic Resonance, Biomolecular–Metabolism
  • Structure-Activity Relationship–Metabolism
  • Cyclic Amp-Dependent Protein Kinases
ispartof: Proceedings of the National Academy of Sciences of the United States of America, April 26, 2011, Vol.108(17), pp.6969-6974
description: 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 pseudo-substrate) 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. allostery | cooperativity | phospholamban | substrate recognition | intrinsically disordered proteins doi/ 10.1073/pnas.1102701108
language: eng
source:
identifier: E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1102701108
fulltext: fulltext
issn:
  • 10916490
  • 1091-6490
url: Link


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titleDynamically committed, uncommitted, and quenched states encoded in protein kinase A revealed by NMR spectroscopy.
creatorMasterson, Larry R ; Shi, Lei ; Metcalfe, Emily ; Gao, Jiali ; Taylor, Susan S ; Veglia, Gianluigi
contributorMasterson, Larry R (correspondence author) ; Masterson, Larry R (record owner)
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identifierE-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1102701108
subjectAllosteric Regulation–Chemistry ; Animals–Genetics ; Catalytic Domain–Metabolism ; Cyclic Amp-Dependent Protein Kinases–Metabolism ; Humans–Metabolism ; Models, Molecular–Metabolism ; Nuclear Magnetic Resonance, Biomolecular–Metabolism ; Structure-Activity Relationship–Metabolism ; Cyclic Amp-Dependent Protein Kinases
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descriptionProtein 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 pseudo-substrate) 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. allostery | cooperativity | phospholamban | substrate recognition | intrinsically disordered proteins doi/ 10.1073/pnas.1102701108
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