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Dynamics of a flexible loop in dihydrofolate-reductase from escherichia-coli and its implication for catalysis

Academic Article
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Overview

authors

  • Falzone, C. J.
  • Wright, Peter
  • Benkovic, S. J.

publication date

  • January 1994

journal

  • Biochemistry  Journal

abstract

  • Apo-dihydrofolate reductase from Escherichia coli samples two distinct environments slowly on the NMR time scale at room temperature. Several assigned resonances belong to residues in, or proximal to, a loop (loop I) which is comprised of residues 9-24. This exchange process was altered (either removed or made fast on the NMR time scale) by deleting three hairpin turn forming residues from the loop and filling the gap with a single glycine [Li, L., Falzone, C. J., Wright, P. E., & Benkovic, S. J. (1992) Biochemistry 31, 7826-7833]. An approximate value of 35 s-1 for the exchange rate associated with loop I in apo-DHFR was obtained in two-dimensional nuclear Overhauser spectra by analyzing the time dependence of the cross-peak volume for N epsilon H of Trp-22, a residue which is located in this loop and which has resolved cross-peaks. Owing to the critical role that this loop plays in catalysis, the correspondence between this rate of conformational exchange and off-rates for tetrahydrofolate and the reduced nicotinamide cofactor from product and substrate complexes suggests that loop movement may be a limiting factor in substrate turnover.

subject areas

  • Catalysis
  • Crystallization
  • Crystallography, X-Ray
  • Escherichia coli
  • Folic Acid
  • Magnetic Resonance Spectroscopy
  • Methotrexate
  • Molecular Structure
  • NADP
  • Protein Conformation
  • Tetrahydrofolate Dehydrogenase
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Identity

International Standard Serial Number (ISSN)

  • 0006-2960

Digital Object Identifier (DOI)

  • 10.1021/bi00168a007

PubMed ID

  • 8286374
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Additional Document Info

start page

  • 439

end page

  • 442

volume

  • 33

issue

  • 2

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