FCCC LOGO Faculty Publications
Lawrence SH , Ramirez UD , Tang L , Fazliyez F , Kundrat L , Markham GD , Jaffe EK
Shape shifting leads to small-molecule allosteric drug discovery
Chem Biol. 2008 Jun;15(6) :586-96
PMID: 18559269   
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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.
Notes
Lawrence, Sarah H Ramirez, Ursula D Tang, Lei Fazliyez, Farit Kundrat, Lenka Markham, George D Jaffe, Eileen K AI 063324/AI/NIAID NIH HHS/United States CA 006927/CA/NCI NIH HHS/United States CA 009035-31/CA/NCI NIH HHS/United States GM 31186/GM/NIGMS NIH HHS/United States R01 ES003654-24/ES/NIEHS NIH HHS/United States R21 AI063324-02/AI/NIAID NIH HHS/United States Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Chemistry & biology Chem Biol. 2008 Jun;15(6):586-96.