1U3R

Crystal Structure of Estrogen Receptor beta complexed with WAY-338

Summary for 1U3R

• Entry DOI: 10.2210/pdb1u3r/pdb
• Related: 1U3Q 1U3S
• Descriptor: Estrogen receptor beta, steroid receptor coactivator-1, 2-(5-HYDROXY-NAPHTHALEN-1-YL)-1,3-BENZOOXAZOL-6-OL, ... (4 entities in total)
• Functional Keywords: estrogen receptor, estrogen receptor beta, er-beta, er, estrogen, nuclear receptor, transcription factor, agonist, transcription
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: Q92731
• Total number of polymer chains: 4
• Total formula weight: 57860.41

Authors

Malamas, M.S.,Manas, E.S.,McDevitt, R.E.,Gunawan, I.,Xu, Z.B.,Collini, M.D.,Miller, C.P.,Dinh, T.,Henderson, R.A.,Keith Jr., J.C.,Harris, H.A. (deposition date: 2004-07-22, release date: 2005-07-26, Last modification date: 2024-02-14)

Primary citation

Malamas, M.S.,Manas, E.S.,McDevitt, R.E.,Gunawan, I.,Xu, Z.B.,Collini, M.D.,Miller, C.P.,Dinh, T.,Henderson, R.A.,Keith Jr., J.C.,Harris, H.A.
Design and synthesis of aryl diphenolic azoles as potent and selective estrogen receptor-beta ligands.
J.Med.Chem., 47:5021-5040, 2004

PubMed Abstract: New diphenolic azoles as highly selective estrogen receptor-beta agonists are reported. The more potent and selective analogues of these series have comparable binding affinities for ERbeta as the natural ligand 17beta-estradiol but are >100-fold selective over ERalpha. Our design strategy not only followed a traditional SAR approach but also was supported by X-ray structures of ERbeta cocrystallized with various ligands as well as molecular modeling studies. These strategies enabled us to take advantage of a single conservative residue substitution in the ligand-binding pocket, ERalpha Met(421) --> ERbeta Ile(373), to optimize ERbeta selectivity. The 7-position-substituted benzoxazoles (Table 5) were the most selective ligands of both azole series, with ERB-041 (117) being >200-fold selective for ERbeta. The majority of ERbeta selective agonists tested that were at least approximately 50-fold selective displayed a consistent in vivo profile: they were inactive in several models of classic estrogen action (uterotrophic, osteopenia, and vasomotor instability models) and yet were active in the HLA-B27 transgenic rat model of inflammatory bowel disease. These data suggest that ERbeta-selective agonists are devoid of classic estrogenic effects and may offer a novel therapy to treat certain inflammatory conditions.

PubMed: 15456246
DOI: 10.1021/jm049719y

Experimental method

X-RAY DIFFRACTION (2.21 Å)