The article explores the structural and molecular basis of interactions between nuclear receptors (NRs) and coactivators, specifically the p160 family of coactivators. The authors focus on the interaction between the thyroid hormone receptor (TRβ) ligand-binding domain (LBD) and the GRIP1 coactivator, which contains three LxxLL motifs. They demonstrate that the interaction is ligand-dependent and involves a hydrophobic groove in the TRβ LBD that interacts with an amphipathic α-helix from GRIP1. The affinity and specificity of this interaction depend on the sequence of the LxxLL motif and adjacent sequences. The study also reveals that different receptors use these structural elements differently, contributing to the differential preferences observed for specific coactivator members. The authors suggest that the combination of these features allows for both flexible and precise assembly of regulatory complexes, which is essential for combinatorial regulation of transcription. The findings provide insights into how NRs and coactivators interact and how specificity is achieved within these complexes.The article explores the structural and molecular basis of interactions between nuclear receptors (NRs) and coactivators, specifically the p160 family of coactivators. The authors focus on the interaction between the thyroid hormone receptor (TRβ) ligand-binding domain (LBD) and the GRIP1 coactivator, which contains three LxxLL motifs. They demonstrate that the interaction is ligand-dependent and involves a hydrophobic groove in the TRβ LBD that interacts with an amphipathic α-helix from GRIP1. The affinity and specificity of this interaction depend on the sequence of the LxxLL motif and adjacent sequences. The study also reveals that different receptors use these structural elements differently, contributing to the differential preferences observed for specific coactivator members. The authors suggest that the combination of these features allows for both flexible and precise assembly of regulatory complexes, which is essential for combinatorial regulation of transcription. The findings provide insights into how NRs and coactivators interact and how specificity is achieved within these complexes.