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Defining the role of active-site loop fluctuations in dihydrofolate reductase catalysis

Academic Article
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Overview

related to degree

  • Schnell, Jason, Ph.D. in Biology, Scripps Research 1997 - 2003

authors

  • McElheny, D.
  • Schnell, Jason
  • Lansing, J. C.
  • Dyson, Jane
  • Wright, Peter

publication date

  • April 2005

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • Dynamic processes are implicit in the catalytic function of all enzymes. To obtain insights into the relationship between the dynamics and thermodynamics of protein fluctuations and catalysis, we have measured millisecond time scale motions in the enzyme dihydrofolate reductase using NMR relaxation methods. Studies of a ternary complex formed from the substrate analog folate and oxidized NADP+ cofactor revealed conformational exchange between a ground state, in which the active site loops adopt a closed conformation, and a weakly populated (4.2% at 30 degrees C) excited state with the loops in the occluded conformation. Fluctuations between these states, which involve motions of the nicotinamide ring of the cofactor into and out of the active site, occur on a time scale that is directly relevant to the structural transitions involved in progression through the catalytic cycle.

subject areas

  • Biophysical Phenomena
  • Biophysics
  • Catalysis
  • Catalytic Domain
  • Escherichia coli
  • Folic Acid
  • Kinetics
  • Models, Biological
  • Models, Molecular
  • NADP
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Conformation
  • Tetrahydrofolate Dehydrogenase
  • Thermodynamics
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Research

keywords

  • NMR relaxation
  • enzyme catalysis
  • hydride transfer
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Identity

PubMed Central ID

  • PMC556001

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.0500699102

PubMed ID

  • 15795383
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Additional Document Info

start page

  • 5032

end page

  • 5037

volume

  • 102

issue

  • 14

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