Structural plasticity in the oestrogen receptor ligand-binding domain.
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.
Nettles
Kendall W
KW
Department of Cancer Biology, The Scripps Research Institute, 5353 Parkside Drive, Jupiter, Florida 33458, USA. knettles@scripps.edu
Bruning
John B
JB
Gil
German
G
O'Neill
Erin E
EE
Nowak
Jason
J
Guo
Yuee
Y
Hughs
Alun
A
Kim
Younchang
Y
DeSombre
Eugene R
ER
Dilis
Robert
R
Hanson
Robert N
RN
Joachimiak
Andrzej
A
Greene
Geoffrey L
GL
D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004958:Estradiol / Q000737:chemistry / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
D047628:Estrogen Receptor alpha; D008024:Ligands; D004958:Estradiol