Unveiling hidden features of orphan nuclear receptors: the case of the small heterodimer partner (SHP).

The small heterodimer partner (SHP) is an atypical nuclear receptor lacking the N-terminal ligand-independent activation domain and the DNA binding domain. SHP acts as transcriptional inhibitor of a large set of nuclear receptors, among which ER, AR, CAR, RXR, GR, LXR and ERRgamma. The repression mechanism of SHP involves several actions including competition with coactivators binding on the AF-2 of nuclear receptors and recruitment of transcriptional inhibitors such as EID-1. The investigation of the structure and repression mechanism of SHP is a challenging task for a full understanding of nuclear receptor interaction pathways and functions. So far, mutational analyses in multiple populations identified loss of function mutants of SHP gene involved in mild obesity, increased birth weight and insulin levels. Furthermore, experimental mutagenesis has been exploited to characterize the interactions between SHP and the transcriptional inhibitor EID-1. With the aim of gaining insight into the structural basis of SHP repression mechanism, we modelled SHP and EID-1 structures. Docking experiments were carried out to identify the EID-1 binding surface on SHP structure. The results obtained in this study allow for the first time a unique interpretation of many experimental data available from the published literature. In addition, a fascinating hypothesis raises from the inspection of the proposed SHP structure: the presence of a potential unexpected ligand binding site, supported by recently available experimental data that may represent a breakthrough in the design and development of synthetic modulators of SHP functions.