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A dynamic knockout reveals that conformational fluctuations influence the chemical step of enzyme catalysis

Academic Article
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Overview

related to degree

  • Bhabha, Gira Sorab, Ph.D. in Biology, Scripps Research 2006 - 2011
  • Ekiert, Damian, Ph.D. in Chemical Biology, Scripps Research 2006 - 2011

authors

  • Bhabha, Gira Sorab
  • Lee, Jiing-Dwan
  • Ekiert, Damian
  • Gam, J.
  • Wilson, Ian
  • Dyson, Jane
  • Benkovic, S. J.
  • Wright, Peter

publication date

  • April 2011

journal

  • Science  Journal

abstract

  • Conformational dynamics play a key role in enzyme catalysis. Although protein motions have clear implications for ligand flux, a role for dynamics in the chemical step of enzyme catalysis has not been clearly established. We generated a mutant of Escherichia coli dihydrofolate reductase that abrogates millisecond-time-scale fluctuations in the enzyme active site without perturbing its structural and electrostatic preorganization. This dynamic knockout severely impairs hydride transfer. Thus, we have found a link between conformational fluctuations on the millisecond time scale and the chemical step of an enzymatic reaction, with broad implications for our understanding of enzyme mechanisms and for design of novel protein catalysts.

subject areas

  • Amino Acid Sequence
  • Biocatalysis
  • Catalytic Domain
  • Crystallography, X-Ray
  • Escherichia coli
  • Folic Acid
  • Kinetics
  • Models, Molecular
  • Molecular Sequence Data
  • Mutant Proteins
  • NADP
  • Protein Conformation
  • Tetrahydrofolate Dehydrogenase
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Identity

PubMed Central ID

  • PMC3151171

International Standard Serial Number (ISSN)

  • 0036-8075

Digital Object Identifier (DOI)

  • 10.1126/science.1198542

PubMed ID

  • 21474759
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Additional Document Info

start page

  • 234

end page

  • 238

volume

  • 332

issue

  • 6026

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