Structural insights into retinoic acid receptor activation and selective modulators

Abstract

Retinoic acid receptors (RARs), including RARα, RARβ and RARγ, serve as essential nuclear receptors that act as transcription factors activated by ligands. They predominantly regulate gene expression and affect various biological processes, including differentiation. Their dysregulation is implicated in various cancers and other diseases, notably acute promyelocytic leukaemia (APL), where the promyelocytic leukemia (PML)‒RARα fusion protein disrupts normal granulocyte maturation. All-trans retinoic acid, which promotes the degradation of this fusion protein is a key therapeutic agent for APL and is also involved in the treatment of other diseases. Recently, various selective RAR modulators targeting specific RAR subtypes have been developed, which show promise in treating cancer and other diseases. The structural biology of RARs reveals how ligand binding induces conformational changes that facilitate co-activator recruitment, thereby modulating transcription. This review explores the crystal structures of RARs in various activation states, detailing RARs’ interactions with retinoid X receptors, ligands, DNA and co-regulators, and emphasises the importance of understanding these mechanisms for the rational design of new RAR-targeted therapies. The potential for developing selective RAR modulators is highlighted, along with the need for comprehensive structural data to enhance our understanding of RAR functions in disease contexts. Future research directions include utilising advanced imaging techniques and artificial intelligence-driven predictions to elucidate the dynamics of RAR complexes, ultimately aiming to translate structural insights into clinical applications for various diseases.