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

   


Authors: Escobar-Alvarez, S.; Goldgur, Y.; Yang, G.; Ouerfelli, O.; Li, Y.; Scheinberg, D. A.
Article Title: Structure and activity of human mitochondrial peptide deformylase, a novel cancer target
Abstract: 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. © 2009 Elsevier Ltd. All rights reserved.
Keywords: neoplasms; mammalia; carboxy terminal sequence; protein binding; amino acid sequence; conserved sequence; molecular sequence data; sequence homology, amino acid; kinetics; mammal; nucleotide sequence; recombinant proteins; substrate specificity; base sequence; binding site; crystal structure; models, molecular; dimerization; crystallography, x-ray; catalysis; dna primers; enzyme kinetics; protein folding; protein structure; enzyme structure; human deformylase; peptide deformylase; actinonin; mitochondrial protein; amidohydrolases; catalytic domain; dna, mitochondrial; mitochondria; oligopeptides; protein structure, quaternary; static electricity
Journal Title: Journal of Molecular Biology
Volume: 387
Issue: 5
ISSN: 0022-2836
Publisher: Academic Press Inc., Elsevier Science  
Date Published: 2009-04-17
Start Page: 1211
End Page: 1228
Language: English
DOI: 10.1016/j.jmb.2009.02.032
PUBMED: 19236878
PROVIDER: scopus
PMCID: PMC2782631
DOI/URL:

http://www.scopus.com/inward/record.url?eid=2-s2.0-63749099831&partnerID=40&md5=d24200945e590c76dfc4150cafac6231
Notes: --- - "Cited By (since 1996): 6" - "Export Date: 30 November 2010" - "CODEN: JMOBA" - "Source: Scopus"
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MSK Authors
  1. David Scheinberg
    499 Scheinberg
  2. Ouathek Ouerfelli
    102 Ouerfelli
  3. Guangli Yang
    34 Yang
  4. Yehuda Goldgur
    42 Goldgur
  5. Yueming Li
    132 Li
  6. Sindy N Escobar Alvarez
    8 Escobar-Alvarez
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