A call to order: Examining structured domains in biomolecular condensates

[Display omitted] •NMR has been extensively used to study proteins undergoing phase separation.•There is an interplay between IDRs and structured domains in condensates.•Structured domains undergoing phase separation are poorly studied.•Conformational landscapes in condensates may reveal new regulatory mechanisms. Diverse cellular processes have been observed or predicted to occur in biomolecular condensates, which are comprised of proteins and nucleic acids that undergo liquid–liquid phase separation (LLPS). Protein-driven LLPS often involves weak, multivalent interactions between intrinsically disordered regions (IDRs). Due to their inherent lack of defined tertiary structures, NMR has been a powerful resource for studying the behavior and interactions of IDRs in condensates. While IDRs in proteins are necessary for phase separation, core proteins enriched in condensates often contain structured domains that are essential for their function and contribute to phase separation. How phase separation can affect the structure and conformational dynamics of structured domains is critical for understanding how biochemical reactions can be effectively regulated in cellular condensates. In this perspective, we discuss the consequences phase separation can have on structured domains and outline NMR observables we believe are useful for assessing protein structure and dynamics in condensates.