Wrangling Shape-Shifting Morpheeins to Tackle Disease and Approach Drug Discovery.

Eileen K Jaffe

doi:10.3389/fmolb.2020.582966

Abstract

Homo-multimeric proteins that can come apart, change shape, and reassemble differently with functional consequences have been called morpheeins and/or transformers; these provide a largely unexplored context for understanding disease and developing allosteric therapeutics. This article describes such proteins within the context of protein structure dynamics, provides one detailed example related to an inborn error of metabolism and potential herbicide development, and describes the context for applying these ideas for understanding disease and designing bioactive molecules, such as therapeutics.

Highlights

A great number of medically relevant proteins are homo-multimers, some of which exist as an equilibrium of alternate assemblies that are both non-additive and functionally distinct
The physiologic relevance of the morpheein model of allostery was first realized for the protein porphobilinogen synthase (PBGS), whose quaternary structure dynamic is illustrated in Figure 2A (Breinig et al, 2003; Selwood et al, 2008)
For the first 20 years that we studied PORPHOBILINOGEN SYNTHASE (PBGS), we were not looking for the fifth level of protein structure

Summary

Introduction

A great number of medically relevant proteins are homo-multimers, some of which exist as an equilibrium of alternate assemblies that are both non-additive and functionally distinct. Because there are so few well characterized examples, even the most comprehensive treatments of allosteric drug discovery do not address proteins that are established to sample a dynamic equilibrium of assemblies comprised of alternate protomer conformations whose interconversion is forbidden within the assemblies (Lu et al, 2019a,b). Both Aye’s and OllmannSaphire’s treatments highlight that normal protein structure dynamics can include architecturally distinct assemblies with alternate functions that are comprised of different protomer conformations.

Results

Conclusion