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Correlation between conformational dynamics and activity in protein kinase A (354.1)
Author(s) -
Veglia Gianluigi
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.354.1
Subject(s) - enzyme , chemistry , kinase , conformational change , protein dynamics , biophysics , protein kinase a , catalytic cycle , dynamics (music) , molecular dynamics , nuclear magnetic resonance spectroscopy , protein structure , biochemistry , microbiology and biotechnology , stereochemistry , biology , computational chemistry , physics , acoustics
Protein kinases mediate a myriad of cell signaling events. Protein kinase A (PKA) is considered the prototypical kinase, sharing its catalytic core (PKA‐C) with many other kinases. Using NMR spectroscopy, we mapped the conformational energy landscape of the kinase. Although incomplete, this study unveils the activation and deactivation processes for this enzyme. We found that conformational dynamics of both backbone and side chains play a critical role in activation and regulation. In particular, backbone conformational dynamics in the slow time scale of NMR are synchronous to the enzyme turnover. While the apo state is dynamically uncommitted, nucleotide defines a dynamically committed state. The binding of inhibitors quench the enzyme’s conformational dynamics, selecting a dynamically quenched state. We also found that enhanced motions via mutations reduce the catalytic efficiency of the kinase. We conclude that the conformational dynamics of the enzyme is linked to the overall turnover, and an increase or decrease of these motions has negative effects on the catalytic cycle.