STRUCTURE AND SPECIFICITY OF NUCLEAR RECEPTOR-COACTIVATOR INTERACTIONS

Combinatorial regulation of transcription implies flexible yet precise assembly of multiprotein regulatory complexes in response to signals. Biochemical and crystallographic analyses revealed that hormone bindi ng leads to the formation of a hydrophobic groove within the ligand bi nding domain (LBD) of the thyroid hormone receptor that interacts with an LxxLL motif-containing alpha-helix from GRIP1, a coactivator. Resi dues immediately adjacent to the motif modulate the affinity of the in teraction; the motif and the adjacent sequences are employed to differ ent extents in binding to different receptors. Such interactions of am phipathic alpha-helices with hydrophobic grooves define protein interf aces in other regulatory complexes as well. We suggest that these comm on structural elements impart flexibility to combinatorial regulation, whereas side chains at the interface impart specificity.