| Autor: |
Lawrence SH; Fox Chase Cancer Center, Philadelphia, PA 19111, USA., Ramirez UD, Tang L, Fazliyez F, Kundrat L, Markham GD, Jaffe EK |
| Jazyk: |
angličtina |
| Zdroj: |
Chemistry & biology [Chem Biol] 2008 Jun; Vol. 15 (6), pp. 586-96. |
| DOI: |
10.1016/j.chembiol.2008.04.012 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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