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

JOURNAL OF MOLECULAR BIOLOGY

卷:387

Article

Escobar-Alvarez, Sindy^1,2  Goldgur, Yehuda³  Yang, Guangli¹  Ouerfelli, Ouathek¹  Li, Yueming¹  Scheinberg, David A.¹ 

[1] Sloan Kettering Inst, Mol Pharmacol & Chem Program, New York, NY 10065 USA

[2] Cornell Univ, Weill Grad Sch Biomed Sci, Dept Pharmacol, New York, NY 10065 USA

[3] Sloan Kettering Inst, Struct Biol Program, New York, NY 10065 USA

关键词: human deformylase;    peptide deformylase;    crystal structure;   

DOI  :  10.1016/j.jmb.2009.02.032

来源: Elsevier

【 摘 要 】

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 angstrom), 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 arid H3), however, shape a characteristic active site entrance. The structure of HsPDF bound to the peptidomimetic inhibitor actinonin (1.7 angstrom) 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. (C) 2009 Elsevier Ltd. All rights reserved.

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