Shape shifting leads to small-molecule allosteric drug discovery.
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.
Lawrence
Sarah H
SH
Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Ramirez
Ursula D
UD
Tang
Lei
L
Fazliyez
Farit
F
Kundrat
Lenka
L
Markham
George D
GD
Jaffe
Eileen K
EK
D000495:Allosteric Site; D000595:Amino Acid Sequence; D000818:Animals; D019281:Dimerization; D015195:Drug Design; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D017386:Sequence Homology, Amino Acid