Mapping a disordered portion of the Brz2001-binding site on a plant monooxygenase, DWARF4, using a quartz-crystal microbalance biosensor-based T7 phage display

Assay Drug Dev Technol. 2013 Apr;11(3):206-15. doi: 10.1089/adt.2012.478. Epub 2013 Mar 20.

Abstract

In small-molecule/protein interaction studies, technical difficulties such as low solubility of small molecules or low abundance of protein samples often restrict the progress of research. Here, we describe a quartz-crystal microbalance (QCM) biosensor-based T7 phage display in combination use with a receptor-ligand contacts (RELIC) bioinformatics server for application in a plant Brz2001/DWARF4 system. Brz2001 is a brassinosteroid biosynthesis inhibitor in the less-soluble triazole series of compounds that targets DWARF4, a cytochrome P450 (Cyp450) monooxygenase containing heme and iron. Using a Brz2001 derivative that has higher solubility in 70% EtOH and forms a self-assembled monolayer on gold electrode, we selected 34 Brz2001-recognizing peptides from a 15-mer T7 phage-displayed random peptide library using a total of four sets of one-cycle biopanning. The RELIC/MOTIF program revealed continuous and discontinuous short motifs conserved within the 34 Brz2001-selected 15-mer peptide sequences, indicating the increase of information content for Brz2001 recognition. Furthermore, an analysis of similarity between the 34 peptides and the amino-acid sequence of DWARF4 using the RELIC/MATCH program generated a similarity plot and a cluster diagram of the amino-acid sequence. Both of these data highlighted an internally located disordered portion of a catalytic site on DWARF4, indicating that this portion is essential for Brz2001 recognition. A similar trend was also noted by an analysis using another 26 Brz2001-selected peptides, and not observed using the 27 gold electrode-recognizing control peptides, demonstrating the reproducibility and specificity of this method. Thus, this affinity-based strategy enables high-throughput detection of the small-molecule-recognizing portion on the target protein, which overcomes technical difficulties such as sample solubility or preparation that occur when conventional methods are used.

MeSH terms

  • Amino Acid Sequence
  • Arabidopsis Proteins / drug effects
  • Arabidopsis Proteins / metabolism*
  • Bacteriophage T7 / genetics*
  • Binding Sites
  • Biosensing Techniques
  • Cytochrome P-450 Enzyme System / drug effects
  • Cytochrome P-450 Enzyme System / metabolism*
  • DNA, Viral / genetics
  • Indicators and Reagents
  • Mixed Function Oxygenases / metabolism*
  • Molecular Sequence Data
  • Peptide Library
  • Polymerase Chain Reaction
  • Reproducibility of Results
  • Software
  • Triazoles / metabolism*
  • Viral Plaque Assay

Substances

  • AT3G50660 protein, Arabidopsis
  • Arabidopsis Proteins
  • Brz2001
  • DNA, Viral
  • Indicators and Reagents
  • Peptide Library
  • Triazoles
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases