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Enzyme flexibility and the catalytic mechanism of farnesyltransferase: targeting the relation

Sérgio F Sousa1, Pedro A Fernandes, Maria João Ramos

  • 1REQUIMTE, Departamento de Química, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre, 687, 4169-007 Porto, Portugal.

The Journal of Physical Chemistry. B
|June 25, 2008
PubMed

Insights

Molecular dynamics simulations reveal how farnesyltransferase enzyme (FTase) flexibility changes during its catalytic mechanism. Small events at the active site cause significant structural changes in distant enzyme regions.

Area of Science:

  • Biochemistry
  • Enzymology
  • Computational Biology

Background:

  • Farnesyltransferase enzyme (FTase) is a key target in anticancer therapy.
  • The precise catalytic mechanism of FTase remains incompletely understood.
  • Farnesyltransferase inhibitors (FTIs) show promise, but mechanistic insights are needed.

Purpose of the Study:

  • To investigate enzyme flexibility in key intermediate states of the FTase catalytic mechanism using molecular dynamics simulations.
  • To elucidate structural and dynamical changes during FPP binding, peptide coordination, and product formation.
  • To understand how active site events propagate to affect the entire enzyme structure.

Main Methods:

  • Application of molecular dynamics (MD) simulations.
  • Analysis of four key intermediate states: FTase resting state, binary complex (FTase-FPP), ternary complex (FTase-FPP-Peptide), and product complex (FTase-Product).
  • Detailed examination of structural and dynamical variations at the enzyme's active site and surrounding regions.

Main Results:

  • Identified variational patterns in enzyme flexibility across different catalytic states.
  • Demonstrated that substrate binding and product formation induce localized changes near the active site.
  • Observed significant conformational changes in external enzyme regions resulting from active site events.

Conclusions:

  • Enzyme flexibility plays a crucial role in the FTase catalytic mechanism.
  • Allosteric effects, initiated at the active site, significantly influence the enzyme's overall dynamics.
  • Understanding these dynamics can inform the design of more effective FTIs for cancer therapy.

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