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Structural plasticity in the oestrogen receptor ligand-binding domain.

ABSTRACT: 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.

SUBMITTER: Nettles KW

PROVIDER: S-EPMC2002528 | biostudies-other | 2007 Jun

REPOSITORIES: biostudies-other

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Structural plasticity in the oestrogen receptor ligand-binding domain.

Nettles Kendall W KW Bruning John B JB Gil German G O'Neill Erin E EE Nowak Jason J Guo Yuee Y Kim Younchang Y DeSombre Eugene R ER Dilis Robert R Hanson Robert N RN Joachimiak Andrzej A Greene Geoffrey L GL

EMBO reports 20070427 6

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 po ...[more]

PMID: 17468738

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