Steroid hormone receptor complex

Sex hormone-binding globulin (SHBG) is thought to mainly function as a transporter and reservoir for the estradiol and testosterone sex hormones. However it has also been demonstrated that SHBG can bind to a cell surface receptor (SHBG-R). The SHBG-R has not been completely characterized. A subset of steroids are able to bind to the SHBG/SHBG-R complex resulting in an activation of adenylyl cyclase and synthesis of the cAMP second messenger. [19] Hence the SHBG/SHBG-R complex appears to act as a transmembrane steroid receptor that is capable of transmitting signals to the interior of cells.

As demonstrated in progesterone receptor-deficient mice, the physiological effects of progesterone depend completely on the presence of the human progesterone receptor (hPR), a member of the steroid-receptor superfamily of nuclear receptors. The single-copy human (hPR) gene uses separate promoters and translational start sites to produce two isoforms, hPR-A and -B, which are identical except for an additional 165 amino acids present only in the N terminus of hPR-B. [12] Although hPR-B shares many important structural domains with hPR-A, they are in fact two functionally distinct transcription factors, mediating their own response genes and physiological effects with little overlap. Selective ablation of PR-A in a mouse model, resulting in exclusive production of PR-B, unexpectedly revealed that PR-B contributes to, rather than inhibits, epithelial cell proliferation both in response to estrogen alone and in the presence of progesterone and estrogen. These results suggest that in the uterus, the PR-A isoform is necessary to oppose estrogen-induced proliferation as well as PR-B-dependent proliferation.

Treatment of human prostate carcinoma-derived LNCaP cells with androgen or oestradiol triggers simultaneous association of androgen receptor and oestradiol receptor beta with Src, activates the Src/Raf-1/Erk-2 pathway and stimulates cell proliferation. Surprisingly, either androgen or oestradiol action on each of these steps is inhibited by both anti-androgens and anti-oestrogens. Similar findings for oestradiol receptor alpha were observed in MCF-7 or T47D cells stimulated by either oestradiol or androgens. Microinjection of LNCaP, MCF-7 and T47D cells with SrcK(-) abolishes steroid-stimulated S-phase entry. Data from transfected Cos cells confirm and extend the findings from these cells. Hormone-stimulated Src interaction with the androgen receptor and oestradiol receptor alpha or beta is detected using glutathione S:-transferase fusion constructs. Src SH2 interacts with phosphotyrosine 537 of oestradiol receptor alpha and the Src SH3 domain with a proline-rich stretch of the androgen receptor. The role of this phosphotyrosine is stressed by its requirement for association of oestradiol receptor alpha with Src and consequent activation of Src in intact Cos cells.

Molecular docking. We adapted the CDOCKER algorithm to find the binding mode for HO-PBDEs to TRβ. CDOCKER is an implementation of a CHARMM (Chemistry at HARvard Macromolecular Mechanics)-based docking tool that has been shown to be viable ( Wu et al. 2003 ). It has been incorporated into Discovery Studio (Accelrys Software Inc., San Diego, CA) through the Dock Ligands (CDOCKER) protocol. We extracted the crystal structure of TRβ (Thyroid receptor beta1 in complex with a beta-selective ligand; PDB ID 1NAX) from the RCSB Protein Data Bank [RCSB (Research Collaboratory for Structural Bioinformatics) PDB; http:///pdb ]. In CDOCKER, random ligand conformations were generated from the initial ligand structure through high-temperature molecular dynamics followed by random rotations. Then, the random conformations were refined by grid-based simulated annealing, which makes the results more accurate. The CDOCKER interaction energy between the ligand and TRβ ( E binding ) was then computed. The docking analysis provided insights into the interactions between the ligands and the receptor, which facilitated the selection of appropriate molecular parameters to characterize the interactions in the QSAR studies.

Steroid hormone receptor complex

steroid hormone receptor complex

Molecular docking. We adapted the CDOCKER algorithm to find the binding mode for HO-PBDEs to TRβ. CDOCKER is an implementation of a CHARMM (Chemistry at HARvard Macromolecular Mechanics)-based docking tool that has been shown to be viable ( Wu et al. 2003 ). It has been incorporated into Discovery Studio (Accelrys Software Inc., San Diego, CA) through the Dock Ligands (CDOCKER) protocol. We extracted the crystal structure of TRβ (Thyroid receptor beta1 in complex with a beta-selective ligand; PDB ID 1NAX) from the RCSB Protein Data Bank [RCSB (Research Collaboratory for Structural Bioinformatics) PDB; http:///pdb ]. In CDOCKER, random ligand conformations were generated from the initial ligand structure through high-temperature molecular dynamics followed by random rotations. Then, the random conformations were refined by grid-based simulated annealing, which makes the results more accurate. The CDOCKER interaction energy between the ligand and TRβ ( E binding ) was then computed. The docking analysis provided insights into the interactions between the ligands and the receptor, which facilitated the selection of appropriate molecular parameters to characterize the interactions in the QSAR studies.

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