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Effect of N-terminal and Met23 mutations on the structure and dynamics of onconase

Vitaliy Y Gorbatyuk1, Cheng-Kun Tsai, Chi-Fon Chang

  • 1Institute of Biomedical Sciences, Academia Sinica, Nankang, Taipei 11529, Taiwan, Republic of China.

The Journal of Biological Chemistry
|December 3, 2003
PubMed

Insights

Recombinant onconase (rONC) exhibits flexibility and structural changes due to mutations, impacting its stability and anticancer potential. These findings offer insights into ranpirnase

Area of Science:

  • Biochemistry
  • Structural Biology
  • Biophysics

Background:

  • Onconase (rONC), a protein with anticancer activity, is undergoing clinical trials for tumor therapy.
  • Understanding the structural dynamics of recombinant onconase is crucial for optimizing its therapeutic efficacy.

Purpose of the Study:

  • To determine the solution NMR structure of recombinant onconase (M-1, Q1, M23L)rONC.
  • To investigate the structural and dynamic differences between wild-type and mutant onconase variants.

Main Methods:

  • Solution Nuclear Magnetic Resonance (NMR) spectroscopy was employed to determine the structure of (M-1, Q1, M23L)rONC.
  • 15N HSQC spectra and model-free analysis of relaxation data (15N-T1, 15N-T2, 15N-1H NOE) were used to assess molecular dynamics.

Main Results:

  • The NMR structure of (M-1, Q1, M23L)rONC was determined, revealing distinct N-terminal residue orientation compared to the x-ray structure.
  • Mutations in onconase induced structural changes and significantly increased flexibility in (M-1, Q1, M23L)rONC compared to E1S-rONC.
  • The alpha1 helix and beta-sheets of (M-1, Q1, M23L)rONC exhibited bending motions, and a key N-terminal hydrogen bond network was absent.

Conclusions:

  • The increased flexibility and altered structural dynamics of (M-1, Q1, M23L)rONC may explain its reduced stability and increased susceptibility to proteases.
  • The findings highlight the impact of specific mutations on onconase structure and dynamics, providing a basis for further therapeutic development.

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