Protein quaternary structure focus for small molecule allosteric control

Abstract

A subset of homo‐oligomeric proteins can reversibly come apart, change conformation in the dissociated state, and reassemble into a structurally and functionally distinct oligomer. Work with the enzyme porphobilinogen synthase has established that this sort of quaternary structure dynamic is physiologically relevant. Proteins that can rearrange in this way are called morpheeins and their quaternary structure dynamic impacts our understanding of protein function and small molecule protein interactions in the following ways. 1) The quaternary structure dynamic of morpheeins can form a structural basis for allostery. 2) Small molecule stabilization of one of the alternate quaternary assemblies defines a new approach to allosteric drug discovery. 3) In addition to functioning as drugs, small molecules that bind to oligomer specific surface cavities will alter the quaternary structure equilibrium and can cause off‐target drug side effects. 4) Naturally occurring mutations can alter the normal quaternary structure equilibrium. This alters normal function and can contribute to disease states. We describe how each of these four impacts has been demonstrated with the morpheein porphobilinogen synthase. We propose additional medically relevant proteins whose behavior suggests that they may function as morpheeins.