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Allostery is an important regulatory phenomenon enabling precise control of biological function. Initial understanding of allostery was gained from seminal work on conformational changes exhibited by structured proteins. Within the last decade, protein allostery has also been demonstrated to occur within intrinsically disordered proteins. This emerging concept of disorder-mediated allostery can be usefully understood in the context of a thermodynamic ensemble. The advantage of this ensemble allosteric model is that it unifies the explanations of allostery occurring within both structured and disordered proteins. One central finding from this model is that energetic coupling, the transmission of a signal between separate regions (or domains) of a protein, is maximized when one or more domains are disordered. This is due to a disorder–order transition that contributes additional coupling energy to the allosteric system through formation of a molecular interaction surface or interface. A second key finding is that multiple interfaces may constructively or destructively interfere with each other, resulting in a new form of allosteric regulation called ‘energetic frustration’. Articulating protein allostery in terms of the thermodynamic ensemble permits formulation of experimentally testable hypotheses which can increase fundamental understanding and direct drug-design efforts. These ideas are illustrated here with the specific case of human glucocorticoid receptor, a medically important multi-domain allosteric protein that contains both structured and disordered regions and exemplifies ‘energetic frustration’. This article is part of a discussion meeting issue ‘Allostery and molecular machines’.

Ensemble allosteric model: energetic frustration within the intrinsically disordered glucocorticoid receptor