Structure and Activity of Human Mitochondrial Peptide Deformylase, a Novel Cancer Target

Sindy Escobar-Alvarez, Yehuda Goldgur, Guangli Yang, Ouathek Ouerfelli, Yueming Li, David A. Scheinberg

Research output: Contribution to journalArticlepeer-review

38 Scopus citations


Peptide deformylase proteins (PDFs) participate in the N-terminal methionine excision pathway of newly synthesized peptides. We show that the human PDF (HsPDF) can deformylate its putative substrates derived from mitochondrial DNA-encoded proteins. The first structural model of a mammalian PDF (1.7 Å), HsPDF, shows a dimer with conserved topology of the catalytic residues and fold as non-mammalian PDFs. The HsPDF C-terminus topology and the presence of a helical loop (H2 and H3), however, shape a characteristic active site entrance. The structure of HsPDF bound to the peptidomimetic inhibitor actinonin (1.7 Å) identified the substrate-binding site. A defined S1′ pocket, but no S2′ or S3′ substrate-binding pockets, exists. A conservation of PDF-actinonin interaction across PDFs was observed. Despite the lack of true S2′ and S3′ binding pockets, confirmed through peptide binding modeling, enzyme kinetics suggest a combined contribution from P2′and P3′ positions of a formylated peptide substrate to turnover.

Original languageEnglish
Pages (from-to)1211-1228
Number of pages18
JournalJournal of Molecular Biology
Issue number5
StatePublished - 17 Apr 2009
Externally publishedYes


  • crystal structure
  • human deformylase
  • peptide deformylase

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology


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