Structural plasticity in the oestrogen receptor ligand-binding domain.

NETTLES KW, GIL G, O'NEILL EE, NOWAK J, GUO Y, KIM Y, DESOMBRE ER, DILIS R, HANSON RN, JOACHIMIAK A, GREENE GL

EMBO REPORTS

NATURE PUBLISHING GROUP

Año: 2007 p. 563 - 568

1469-221X

The steroid hormone receptors are characterized by binding to relatively rigid, inflexible endogenous steroid ligands. Other members of the nuclear receptor superfamily bind to conformationally flexible lipids and show a corresponding degree of elasticity in the ligand-binding pocket. Here, we report the X-ray crystal structure of the oestrogen receptor alpha (ERalpha) bound to an oestradiol derivative with a prosthetic group, ortho- trifluoromethlyphenylvinyl, which binds in a novel extended pocket in the ligand-binding domain. Unlike ER antagonists with bulky side groups, this derivative is enclosed in the ligand-binding pocket, and acts as a potent agonist. This work shows that steroid hormone receptors can interact with a wider array of pharmacophores than previously thought through structural plasticity in the ligand-binding pocket.