Postdoctoral position Small Molecules that Repartition RNA Conformational Ensembles

A one-year postdoc position is open in the RNA Structural Dynamics Group at the Groningen Biomolecular Sciences and Biotechnology Institute (GBB). The appointment will focus on RNA molecules rarely adopt a single structure. Most fold into an ensemble of interconverting conformations, and the balance between these states is often what determines whether an RNA is translated, spliced, degraded or recognised by its partners. RNA has therefore emerged as a major, largely untapped class of drug targets. Yet despite substantial investment, only one small molecule acting on an mRNA (risdiplam) has reached the clinic, and most compounds identified in binding-based screens have no measurable effect on RNA function. Our recent work suggests why. In a study published in Nature Communications (Zhang et al., 2026), we showed that the FDA-approved anticancer drug mitoxantrone does not simply bind its target RNA: it selectively stabilises one conformation within the RNA’s structural ensemble, repartitioning the population of states and thereby modulating RNA function. Binding to RNA is not enough: changing its shape is what makes a drug work. This points to a different route for RNA-targeted drug discovery, in which compounds are selected not for affinity alone but for their ability to redistribute conformational ensembles in a desired direction. This project will build on that framework. Combining high-throughput RNA structure probing (SHAPE/DMS mutational profiling), ensemble deconvolution, chemical biology and functional assays in cells, the postdoctoral researcher will establish how small molecules reshape RNA conformational landscapes, identify new ensemble-repartitioning compounds, and define the rules that connect a shift in the structural ensemble to a change in RNA function.