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Structure and activity of human mitochondrial peptide deformylase, a novel cancer target

Sindy Escobar-Alvarez1, Yehuda Goldgur, Guangli Yang

  • 1Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, 415 E. 68th Street Zuckerman Z1941, New York, NY 10065, USA.

Journal of Molecular Biology
|February 25, 2009
PubMed

Insights

Human peptide deformylase (HsPDF) removes N-terminal methionine from mitochondrial peptides. Structural analysis reveals unique active site features and substrate binding, guiding inhibitor design.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Molecular Biology

Background:

  • Peptide deformylase (PDF) proteins are crucial for N-terminal methionine excision in newly synthesized peptides.
  • Human PDF (HsPDF) is investigated for its role in processing mitochondrial DNA-encoded proteins.

Purpose of the Study:

  • To elucidate the structural characteristics of human PDF (HsPDF).
  • To identify the substrate-binding site and interactions within HsPDF.
  • To understand the mechanism of HsPDF in peptide deformylation.

Main Methods:

  • X-ray crystallography was used to determine the structure of HsPDF and its complex with actinonin at 1.7 Å resolution.
  • Peptide binding modeling and enzyme kinetics were employed to analyze substrate interactions.

Main Results:

  • The first structural model of mammalian PDF (HsPDF) reveals a dimer with conserved catalytic residues and a unique active site entrance shaped by its C-terminus and a helical loop.
  • The structure of HsPDF bound to actinonin identified a defined S1' pocket but lacked S2' and S3' pockets.
  • Enzyme kinetics and modeling suggest that P2' and P3' positions of formylated peptide substrates contribute to turnover despite the absence of dedicated binding pockets.

Conclusions:

  • HsPDF possesses a distinct active site architecture compared to non-mammalian PDFs.
  • The substrate-binding site is primarily defined by the S1' pocket, with broader interactions influencing enzyme activity.
  • Structural insights into HsPDF-actinonin interaction provide a basis for developing targeted inhibitors.

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