In addition, evidence of support for androgen-independent Independent activation of AR through crosstalk caused by cytokines factors. Evidence that NF-jB AR expression and the growth of prostate cancer and MPC-3100 regulates nnte k Contr L is the progression of prostate cancer to androgen-independent Ngigen growth. Yemelyanov et al. found that IKKb kinase, a ma the regulation of the activation of NF JB is constitutively active in tissue samples of metastatic prostate cancer. The AR is NEN from three domains: N-terminal domain ne, the DNA-binding Dom ne and a C-terminal ligand-binding function, a highly conserved ligand-dependent Independent transactivation 2 contains lt On the binding of androgens to the hormone-binding pocket, helix C-terminal T 12 disposed over the bag to the functional surface Perform che AF second The crystal structures of AR LBD in complex with a number of ligands gel Were st. The crystal structures of mutant AR LBD in complex with bicalutamide and hydroxyflutamide obtained, but both are in the form of the receptor agonist. It should be noted that the binding affinity t is not sufficient to account for ligand property antagonist. For example, the mutation entered Born W741L erh Ht twice the binding affinity t of bicalutamide, but the mutation of an AR antagonist bicalutamide in an AR agonist GE Changed. To date there is no crystal structure of AR LBD of the antagonistic form. The structural basis of AR antagonism is unclear. In this work, given the structural conservation among receptors stero Dian, we decided to use the wealth of crystal structures of the estrogen receptor in complex with a number of ER agonists and antagonists LBD.
We suspect that for structural studies of ER in complex with agonists and antagonists, k Nnte light on the AR antagonism Vergie S. Zun Highest, we constructed a structural model of wild-type AR-LBD in complex with bicalutamide, with the crystal structure Acquire ra complexed with hydroxytamoxifen as a model for the LBD H12, d, secondly, to include new information on the antagonism of ERa, we conducted Comparative structural analysis of the ERA in the complex with a number of ER agonists and antagonists LBD. We found residues D351 and L354 in the helix 3 individually assume conformations that are shared by all the complex time-shared, LBD antagonist, but not ERa LBD complex agonists, the distance between D351 and L354 are used k Nnten marker for the antagonistic ERa LBD complex. It is our model WTbicalutamide F Promotion even a marker antagonists, put forth by molecular dynamics simulations of the AR-LBD in complex with hydroxyflutamide or bicalutamide, third, was supported by virtual screening using the model and WTbicalutamide vitro, we found a novel antiandrogen effective against the WT and mutant T877A, W741C and H874Y ARs. This anti-androgen was found to have a dual role in the inhibition of both AR and IKKb. Materials and methods to build structural model of the WT AR LBD in complex with bicalutamide, a structural model of the WT AR LBD in complex with bicalutamide, we have the following three crystal structures as templates: the AR LBD DHT for residues 669 and 907 876 919, the LBD W741L mutant AR in complex with bicalutamide for Residues 710 740 walls, and the ra LBD hydr.