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PDBsum entry 1vjb

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protein ligands Protein-protein interface(s) links
Transcription PDB id
1vjb
Jmol
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, err gamma-2. Engineered: yes
Source: Mus musculus. House mouse. Organism_taxid: 10090. Gene: esrrg, nr3b3, errg2, err3, kiaa0832. 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    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P62508  (ERR3_HUMAN) -  Estrogen-related receptor gamma
Seq:
Struc:
458 a.a.
208 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     nucleus   1 term 
  Biological process     steroid hormone mediated signaling pathway   2 terms 
  Biochemical function     DNA binding     4 terms  

 

 
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.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
23192231 G.Deblois, and V.Giguère (2013).
Oestrogen-related receptors in breast cancer: control of cellular metabolism and beyond.
  Nat Rev Cancer, 13, 27-36.  
20135221 M.Koh, and S.B.Park (2011).
Computer-aided design and synthesis of tetra-aryl-substituted alkenes and their bioevaluation as a selective modulator of estrogen-related receptor γ.
  Mol Divers, 15, 69-81.  
20063036 A.le Maire, W.Bourguet, and P.Balaguer (2010).
A structural view of nuclear hormone receptor: endocrine disruptor interactions.
  Cell Mol Life Sci, 67, 1219-1237.
PDB code: 3kwy
  20957188 J.T.Bridgham, G.N.Eick, C.Larroux, K.Deshpande, M.J.Harms, M.E.Gauthier, E.A.Ortlund, B.M.Degnan, and J.W.Thornton (2010).
Protein evolution by molecular tinkering: diversification of the nuclear receptor superfamily from a ligand-dependent ancestor.
  PLoS Biol, 8, 0.  
20542892 X.Liu, A.Matsushima, H.Okada, and Y.Shimohigashi (2010).
Distinction of the binding modes for human nuclear receptor ERRgamma between bisphenol A and 4-hydroxytamoxifen.
  J Biochem, 148, 247-254.  
19884658 D.H.Volle, M.Decourteix, E.Garo, J.McNeilly, P.Fenichel, J.Auwerx, A.S.McNeilly, K.Schoonjans, and M.Benahmed (2009).
The orphan nuclear receptor small heterodimer partner mediates male infertility induced by diethylstilbestrol in mice.
  J Clin Invest, 119, 3752-3764.  
19090659 G.Bottegoni, I.Kufareva, M.Totrov, and R.Abagyan (2009).
Four-dimensional docking: a fast and accurate account of discrete receptor flexibility in ligand docking.
  J Med Chem, 52, 397-406.  
19520971 N.Koitabashi, D.Bedja, A.L.Zaiman, Y.M.Pinto, M.Zhang, K.L.Gabrielson, E.Takimoto, and D.A.Kass (2009).
Avoidance of transient cardiomyopathy in cardiomyocyte-targeted tamoxifen-induced MerCreMer gene deletion models.
  Circ Res, 105, 12-15.  
18175308 C.Schalon, J.S.Surgand, E.Kellenberger, and D.Rognan (2008).
A simple and fuzzy method to align and compare druggable ligand-binding sites.
  Proteins, 71, 1755-1778.  
18617990 D.G.Teotico, M.L.Frazier, F.Ding, N.V.Dokholyan, B.R.Temple, and M.R.Redinbo (2008).
Active nuclear receptors exhibit highly correlated AF-2 domain motions.
  PLoS Comput Biol, 4, e1000111.  
18927192 E.Bonnelye, N.Laurin, P.Jurdic, D.A.Hart, and J.E.Aubin (2008).
Estrogen receptor-related receptor-alpha (ERR-alpha) is dysregulated in inflammatory arthritis.
  Rheumatology (Oxford), 47, 1785-1791.  
  18197296 H.Okada, T.Tokunaga, X.Liu, S.Takayanagi, A.Matsushima, and Y.Shimohigashi (2008).
Direct evidence revealing structural elements essential for the high binding ability of bisphenol A to human estrogen-related receptor-gamma.
  Environ Health Perspect, 116, 32-38.  
18974135 R.B.Riggins, J.P.Lan, Y.Zhu, U.Klimach, A.Zwart, L.R.Cavalli, B.R.Haddad, L.Chen, T.Gong, J.Xuan, S.P.Ethier, and R.Clarke (2008).
ERRgamma mediates tamoxifen resistance in novel models of invasive lobular breast cancer.
  Cancer Res, 68, 8908-8917.  
18375192 W.A.Alaynick (2008).
Nuclear receptors, mitochondria and lipid metabolism.
  Mitochondrion, 8, 329-337.  
18174917 A.M.Tremblay, and V.Giguère (2007).
The NR3B subgroup: an ovERRview.
  Nucl Recept Signal, 5, e009.  
17001097 L.Banci, I.Bertini, S.Cusack, R.N.de Jong, U.Heinemann, E.Y.Jones, F.Kozielski, K.Maskos, A.Messerschmidt, R.Owens, A.Perrakis, A.Poterszman, G.Schneider, C.Siebold, I.Silman, T.Sixma, G.Stewart-Jones, J.L.Sussman, J.C.Thierry, and D.Moras (2006).
First steps towards effective methods in exploiting high-throughput technologies for the determination of human protein structures of high biomedical value.
  Acta Crystallogr D Biol Crystallogr, 62, 1208-1217.  
16914190 P.Ascenzi, A.Bocedi, and M.Marino (2006).
Structure-function relationship of estrogen receptor alpha and beta: impact on human health.
  Mol Aspects Med, 27, 299-402.  
15723037 E.A.Ortlund, Y.Lee, I.H.Solomon, J.M.Hager, R.Safi, Y.Choi, Z.Guan, A.Tripathy, C.R.Raetz, D.P.McDonnell, D.D.Moore, and M.R.Redinbo (2005).
Modulation of human nuclear receptor LRH-1 activity by phospholipids and SHP.
  Nat Struct Mol Biol, 12, 357-363.
PDB code: 1yuc
15709961 K.W.Nettles, and G.L.Greene (2005).
Ligand control of coregulator recruitment to nuclear receptors.
  Annu Rev Physiol, 67, 309-333.  
15883633 N.Laflamme, S.Giroux, J.C.Loredo-Osti, L.Elfassihi, S.Dodin, C.Blanchet, K.Morgan, V.Giguère, and F.Rousseau (2005).
A frequent regulatory variant of the estrogen-related receptor alpha gene associated with BMD in French-Canadian premenopausal women.
  J Bone Miner Res, 20, 938-944.  
16359432 R.J.Fletterick (2005).
Molecular modelling of the androgen receptor axis: rational basis for androgen receptor intervention in androgen-independent prostate cancer.
  BJU Int, 96, 2-9.  
15610734 L.Shan, J.Vincent, J.S.Brunzelle, I.Dussault, M.Lin, I.Ianculescu, M.A.Sherman, B.M.Forman, and E.J.Fernandez (2004).
Structure of the murine constitutive androstane receptor complexed to androstenol: a molecular basis for inverse agonism.
  Mol Cell, 16, 907-917.
PDB code: 1xnx
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.