Display Settings:

Format

Send to:

Choose Destination
    Chem Biol. 2008 Jun;15(6):586-96.

    Shape shifting leads to small-molecule allosteric drug discovery.

    Source

    Fox Chase Cancer Center, Philadelphia, PA 19111, USA.

    Abstract

    Enzymes that regulate their activity by modulating an equilibrium of alternate, nonadditive, functionally distinct oligomeric assemblies (morpheeins) constitute a recently described mode of allostery. The oligomeric equilibrium for porphobilinogen synthase (PBGS) consists of high-activity octamers, low-activity hexamers, and two dimer conformations. A phylogenetically diverse allosteric site specific to hexamers is proposed as an inhibitor binding site. Inhibitor binding is predicted to draw the oligomeric equilibrium toward the low-activity hexamer. In silico docking enriched a selection from a small-molecule library for compounds predicted to bind to this allosteric site. In vitro testing of selected compounds identified one compound whose inhibition mechanism is species-specific conversion of PBGS octamers to hexamers. We propose that this strategy for inhibitor discovery can be applied to other proteins that use the morpheein model for allosteric regulation.

    PMID:
    18559269
    [PubMed - indexed for MEDLINE]
    PMCID: PMC2703447
    Free PMC Article

    Images from this publication.See all images (5) Free text

    Figure 4
    Figure 5
    Figure 3
    Figure 1
    Figure 2

      Supplemental Content

      Click here to read Click here to read

      Recent activity

      Your browsing activity is empty.

      Activity recording is turned off.

      Turn recording back on

      See more...
      Write to the Help Desk