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Unraveling the three-metal-ion catalytic mechanism of the DNA repair enzyme endonuclease iv

Academic Article
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Overview

authors

  • Ivanov, I.
  • Tainer, John
  • McCammon, J. A.

publication date

  • January 2007

journal

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

abstract

  • Endonuclease IV belongs to a class of important apurinic/apyrimidinic endonucleases involved in DNA repair. Although a structure-based mechanistic hypothesis has been put forth for this enzyme, the detailed catalytic mechanism has remained unknown. Using thermodynamic integration in the context of ab initio quantum mechanics/molecular mechanics molecular dynamics, we examined certain aspects of the phosphodiester cleavage step in the mechanism. We found the reaction proceeded through a synchronous bimolecular (A(N)D(N)) mechanism with reaction free energy and barrier of -3.5 and 20.6 kcal/mol, in agreement with experimental estimates. In the course of the reaction the trinuclear active site of endonuclease IV underwent dramatic local conformational changes: shifts in the mode of coordination of both substrate and first-shell ligands. This qualitative finding supports the notion that structural rearrangements in the active sites of multinuclear enzymes are integral to biological function.

subject areas

  • Binding Sites
  • Catalysis
  • Crystallography, X-Ray
  • DNA
  • DNA Repair
  • Deoxyribonuclease IV (Phage T4-Induced)
  • Escherichia coli
  • Ions
  • Ligands
  • Models, Chemical
  • Models, Molecular
  • Nucleic Acid Conformation
  • Protons
  • Temperature
  • Thermodynamics
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Research

keywords

  • ab initio molecular dynamics
  • base excision repair
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Identity

PubMed Central ID

  • PMC1780068

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.0603468104

PubMed ID

  • 17242363
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Additional Document Info

start page

  • 1465

end page

  • 1470

volume

  • 104

issue

  • 5

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