 |
PDBsum entry 1vjb
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Transcription
|
PDB id
|
|
|
|
1vjb
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Structural basis for the deactivation of the estrogen-Related receptor gamma by diethylstilbestrol or 4-Hydroxytamoxifen and determinants of selectivity.
|
|
|
Authors
|
|
H.Greschik,
R.Flaig,
J.P.Renaud,
D.Moras.
|
|
|
Ref.
|
|
J Biol Chem, 2004,
279,
33639-33646.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
The estrogen-related receptor (ERR) gamma behaves as a constitutive activator of
transcription. Although no natural ligand is known, ERRgamma is deactivated by
the estrogen receptor (ER) agonist diethylstilbestrol and the selective ER
modulator 4-hydroxytamoxifen but does not significantly respond to estradiol or
raloxifene. Here we report the crystal structures of the ERRgamma ligand binding
domain (LBD) complexed with diethylstilbestrol or 4-hydroxytamoxifen. Antagonist
binding to ERRgamma results in a rotation of the side chain of Phe-435 that
partially fills the cavity of the apoLBD. The new rotamer of Phe-435 displaces
the "activation helix" (helix 12) from the agonist position observed
in the absence of ligand. In contrast to the complexes of the ERalpha LBD with
4-hydroxytamoxifen or raloxifene, helix 12 of antagonist-bound ERRgamma does not
occupy the coactivator groove but appears to be completely dissociated from the
LBD body. Comparison of the ligand-bound LBDs of ERRgamma and ERalpha reveals
small but significant differences in the architecture of the ligand binding
pockets that result in a slightly shifted binding position of diethylstilbestrol
and a small rotation of 4-hydroxytamoxifen in the cavity of ERRgamma relative to
ERalpha. Our results provide detailed molecular insight into the conformational
changes occurring upon binding of synthetic antagonists to the constitutive
orphan receptor ERRgamma and reveal structural differences with ERs that explain
why ERRgamma does not bind estradiol or raloxifene and will help to design new
selective antagonists.
|
|
|
|
|
|
|
|
Figure 3.
FIG. 3. Comparison of the LBPs of ERR  and ER  . A,
superimposition of selected parts of the ERR LBD·DES complex
(green) with the ER LBD·DES complex
(red) (PDB code 3ERD [PDB]
). Although the overall ligand binding mode is very similar in
both complexes, the DES binding position is shifted by about 0.5
Å in the cavity of ERR relative to ER . In
contrast to ERR , H12 of the ER LBD can
occupy the agonist position since there is no steric clash with
Leu-525 (corresponding to Phe-435 in ERR ). B, superimposition
of selected parts of the ERR LBD·4-OHT
complex (orange) with the ER LBD·4-OHT
complex (blue) (PDB code 3ERT [PDB]
). In ERR , the 4-OHT binding
position is slightly rotated and mainly differs around the B
ring and the amine moiety. The altered 4-OHT binding results
from steric constraints imposed by Leu-345 (Ile-424 in ER ), a
slightly shifted relative position of H7, and the side chain of
Phe-435 (Leu-525 in ER ). C, left,
superimposition of 4-OHT (blue), E2 (light gray), and RAL
(black) as observed in the LBP of the respective ER complexes (PDB codes:
ER /E2, 1ERE [PDB]
; ER /RAL, 1ERR [PDB]
). Right, superimposition of 4-OHT as observed in the cavity of
ERR (orange) with E2 (light
gray) and RAL (brown) bound to ER . E2 and RAL protrude
deeper into the cavity of ER than 4-OHT and do not
bind to ERR due to insufficient
space in the LBP.
|
|
Figure 4.
FIG. 4. Interactions of H12 with the coactivator groove in
the ER LBD·4-OHT and
the ERR LBD·4-OHT
complex (crystal form 1). A, fitting of the fortuitously
co-crystallized cholic acid molecule into a 2F[o] - F[c]
electron density map. B, superimposition of selected parts of
the ERR LBD (orange) and the ER
LBD
(blue) bound to 4-OHT. In the ER LBD·4-OHT
complex, H12 packs against the coactivator cleft of the
respective LBD body with Leu-536 and Leu-540, mimicking LXXLL
coactivator interactions. In the ERR LBD·4-OHT
complex (subunit B in crystal form 1), H12 interacts with the
coactivator groove of a neighboring molecule. Binding is
distinct from that in ER due to the absence of a
LXXLL motif in H12 of ERR . The alternative
packing interactions between H12 and the coactivator groove,
rather, are determined by the fortuitously co-crystallized
cholic acid molecule that occupies part of the cleft.
|
|
|
|
|
|
The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2004,
279,
33639-33646)
copyright 2004.
|
|
|
|
|
|
|
