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Invited
Speaker The morpheein model of allosteric regulation
can be applied to the discovery of small molecule allosteric modulators
of protein function. Morpheeins are homo-oligomeric proteins where
the oligomer can dissociate, the dissociated units can change conformation,
and the altered conformational state can reassociate to a structurally
and functionally distinct oligomer, as illustrated using a morphing
dice analogy. This phenomenon serves as a basis for allostery [1,2],
as a basis for conformational diseases [3], as a basis for drug discovery
[4], and may be applicable to personalized medicine in the prediction
of drug side effects [5]. Each of these relationships has been established
for the prototype morpheein porphobilinogen synthase where the conformational
disease is a porphyria and the drug application is antimicrobial.
These data will be presented along with a discussion of other drug
targets for which the morpheein model of allostery may apply. Such
targets include HIV integrase, TNFα,
and β-tryptase.
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