Distinct conformational states of nuclear receptor–bound CRSP–Med complexes

The human CRSP–Med coactivator complex is targeted by a diverse array of sequence-specific regulatory proteins. Using EM and single-particle reconstruction techniques, we recently completed a structural analysis of CRSP–Med bound to VP16 and SREBP-1a. Notably, these activators induced distinct conformational states upon binding the coactivator. Ostensibly, these different conformational states result from VP16 and SREBP-1a targeting distinct subunits in the CRSP–Med complex. To test this, we conducted a structural analysis of CRSP–Med bound to either thyroid hormone receptor (TR) or vitamin D receptor (VDR), both of which interact with the same subunit (Med220) of CRSP–Med. Structural comparison of TR- and VDR-bound complexes (at a resolution of 29 Å) indeed reveals a shared conformational feature that is distinct from other known CRSP– Med structures. Importantly, this nuclear receptor–induced structural shift seems largely dependent on the movement of Med220 within the complex.