Allostery and binding cooperativity of the catalytic subunit of protein kinase a by NMR spectroscopy and molecular dynamics simulations

Larry R. Masterson, Alessandro Cembran, Lei Shi, Gianluigi Veglia

Research output: Chapter in Book/Report/Conference proceedingChapter

31 Scopus citations

Abstract

The catalytic subunit of cAMP-dependent protein kinase A (PKA-C) is an exquisite example of a single molecule allosteric enzyme, where classical and modern views of allosteric signaling merge. In this chapter, we describe the mapping of PKA-C conformational dynamics and allosteric signaling in the free and bound states using a combination of NMR spectroscopy and molecular dynamics simulations. We show that ligand binding affects the enzyme's conformational dynamics, shaping the free-energy landscape toward the next stage of the catalytic cycle. While nucleotide and substrate binding enhance the enzyme's conformational entropy and define dynamically committed states, inhibitor binding attenuates the internal dynamics in favor of enthalpic interactions and delineates dynamically quenched states. These studies support a central role of conformational dynamics in many aspects of enzymatic turnover and suggest future avenues for controlling enzymatic function.

Original languageEnglish (US)
Title of host publicationAdvances in Protein Chemistry and Structural Biology
PublisherAcademic Press Inc.
Pages363-389
Number of pages27
DOIs
StatePublished - 2012

Publication series

NameAdvances in Protein Chemistry and Structural Biology
Volume87
ISSN (Print)1876-1623

Bibliographical note

Funding Information:
This work was supported by the NIH grants GM72701 and GM 100310 to G. V. and T32DE007288 to L. R. M. NMR data were collected at NMRFAM (NIH: P41RR02301, P41GM66326, RR02781, and RR08438; NSF: DMB-8415048, OIA-9977486, BIR-9214394) and the U. of Minnesota NMR Facility (NSF BIR-961477). Modeling and calculations were carried out at the Minnesota Supercomputing Institute.

Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.

Keywords

  • Allostery
  • Extended conformational selection
  • Phospholamban
  • Phosphorylation
  • Protein kinase A
  • Substrate recognition

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