Fig. 6

Schematic representation of VDRRXRα heterodimer activation by different ligand and DNA. Protein stabilization induced by interactions of the ligand, DNA and SRC1 RID (as measured by the differential HDX profiles) is shown in blue and green color, whereas destabilization is shown in yellow color. Regions with no significant change are colored gray. VDRRXRα heterodimer is shown with co-receptors’ LBDs including AF2, hinge domains, and DBDs. Allosteric intra-molecular and inter-molecular communications within co-receptors are indicated by black dotted arrow. a Synthetic agonists; Cmpd’s 1 and 2, induce greater stabilization in VDR LBD compared to that of a natural ligand 1,25D3. VDRM Cmpd3 exhibits relatively weak stabilization within AF2. Binding of all ligands induce allosteric destabilization within the VDR DBD. Additional stabilization was observed within the VDR hinge and H3 of RXRα upon binding to Cmpd3. The heterodimer interface becomes more stable upon ligand binding. b Binding of 1,25D3-bound heterodimer to DR3 and DR3 half-site result in stabilization within the DBDs and VDR hinge. Interaction with DR3 half-site leads to intra-domain allosteric stabilization in VDR LBD and AF2 that are not observed upon DR3 binding. In contrast, the presence of synthetic agonist and DNA with heterodimer drive stabilization in the DBD and hinge of both co-receptors and VDR AF2. c Large stabilization was observed in VDR AF2 upon binding SRC1 RID, whereas stabilization in RXRα AF2 was only observed when heterodimer is bound to synthetic agonist and DNA. d Cmpd3 could modulate heterodimer dynamics in an alternative mechanism, in which allosteric stabilization in VDR AF2 occurs upon heterodimer binding to TRPV6 rather than BGLAP. In contrast, neither BGLAP nor TRPV6 alter the conformational of VDR LBD when VDRRXR heterodimer is bound with 1,25D3. e Binding of SRC1 RID results in less stabilization at VDR AF2 when heterodimer is associated with Cmpd3 and TRPV6