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

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