Structure and Activity of Human Mitochondrial Peptide Deformylase, a Novel Cancer Target
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- 作者：Sindy Escobar-Alvarez ; Yehuda Goldgur ; Guangli Yang ; Ouathek Ouerfelli ; Yueming Li ; David A. Scheinberg
- 关键词：human deformylase ; peptide deformylase ; crystal structure
- 刊名：Journal of Molecular Biology
- 出版年：2009
- 出版时间：17 April 2009
- 年：2009
- 卷：387
- 期：5
- 页码：1211-1228
- 全文大小：1157 K
文摘
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.