Structure and functions of the N-terminal domain of steroid hormone receptors

The steroid hormone receptors (SHRs) belong to the large superfamily of nuclear receptors that selectively modulate gene expression in response to specific hormone ligands. The SHRs are required in a broad range of normal physiological processes as well as associated with numerous pathological conditions. Over years, the understanding of the SHR biology and mechanisms of their actions on target cells have found many clinical applications and management of various endocrine-related disorders. However, the effectiveness of SHR-based therapies in endocrine-related cancers remain a clinical challenge. This, in part, is due to the lack of in-depth understanding of structural dynamics and functions of SHRs' intrinsically disordered N-terminal domain (NTD). Recent progress in delineating SHR structural information and their correlations with receptor action in a highly dynamic environment is ultimately helping to explain how diverse SHR signaling mechanisms can elicit selective biological effects. Recent developments are providing new insights of how NTD's structural flexibility plays an important role in SHRs' allosteric regulation leading to the fine tuning of target gene expression to more precisely control SHRs' cell/tissue-specific functions. In this review article, we are discussing the up-to-date knowledge about the SHR actions with a particular emphasis on the structure and functions of the NTD.