The Allosteric Revolution: From Static Structures to Conformational Ensembles and Next-Generation Therapeutics.

The rapid emergence of breakthrough allosteric drugs, together with increasing emphasis on the molecular mechanisms of disease, underscores the critical importance of understanding biological processes at the molecular level. Among these, few concepts are as fundamental as the allosteric behavior of proteins. The importance of allostery was recognized decades ago; however, at the time proteins were viewed as static molecular structures rather than dynamic conformational ensembles that continuously interconvert among states with distinct free energies. The realization that proteins exist as dynamic conformational ensembles has transformed our understanding of oncogenic mutations, molecular recognition, protein regulation, and folding. These processes arise from the intrinsic allosteric nature of proteins embodied in their dynamic conformational ensembles. This conceptual advance has also accelerated the development of allosteric therapeutics. Here, we review the conceptual evolution of allostery from classical models to the conformational ensemble paradigm and discuss its implications for biology and modern drug discovery. We highlight breakthroughs in allosteric therapeutics, including a PROTAC that induces degradation of the Cyclin E-CDK2 complex; the pan-Ras molecular glue daraxonrasib for pancreatic cancer, whose allosteric mechanism is mediated through cyclophilin A rather than directly on Ras; a COP9 signalosome exosite-targeting agent; and other emerging modalities.