PDBsum entry 1vjb

Transcription

PDB id: 1vjb

Contents

Protein chains

208 a.a. *

Ligands

OHT ×2

* Residue conservation analysis

PDB id:

1vjb

Name:

Transcription

Title:

Crystal structure of the ligand-binding domain of the estrogen-related receptor gamma in complex with 4-hydroxytamoxifen

Structure:

Estrogen-related receptor gamma. Chain: a, b. Synonym: estrogen receptor-related protein 3,nuclear receptor subfamily 3 group b member 3. Engineered: yes

Source:

Mus musculus. Mouse. Organism_taxid: 10090. Gene: esrrg, err3, kiaa0832, nr3b3. Expressed in: escherichia coli. Expression_system_taxid: 562.

Biol. unit:

Dimer (from PQS)

Resolution:

3.20Å R-factor: 0.256 R-free: 0.275

Authors:

H.Greschik,R.Flaig,J.P.Renaud,D.Moras

Key ref:

H.Greschik et al. (2004). Structural basis for the deactivation of the estrogen-related receptor gamma by diethylstilbestrol or 4-hydroxytamoxifen and determinants of selectivity. J Biol Chem, 279, 33639-33646. PubMed id: 15161930 DOI: 10.1074/jbc.M402195200

Date:

03-Feb-04 Release date: 08-Jun-04

Protein chains

P62508  (ERR3_HUMAN) -  Estrogen-related receptor gamma from Homo sapiens

Seq: 458 a.a.

Struc: 208 a.a.

DOI no: 10.1074/jbc.M402195200

J Biol Chem 279:33639-33646 (2004)

PubMed id: 15161930

Structural basis for the deactivation of the estrogen-related receptor gamma by diethylstilbestrol or 4-hydroxytamoxifen and determinants of selectivity.

H.Greschik, R.Flaig, J.P.Renaud, D.Moras.

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.

Selected figure(s)

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.

Figures were selected by the author.