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Division of the Clinical Immunology, the Advanced Clinical Research Center, the Institute of Medical Science, the University of Tokyo, Tokyo 108-8639; and the Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo 101-0062, Japan
Address all correspondence and requests for reprints to: Hirotoshi Tanaka, M.D., Ph.D., the Division of the Clinical Immunology, the Advanced Clinical Research Center, the Institute of Medical Science, the University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. E-mail: hirotnk{at}ims.u-tokyo.ac.jp.
Recent structural analyses of the nuclear receptors establish a paradigm of receptor activation, in which agonist binding induces the ligand binding domain (LBD)/activation function-2 helix to form a charge clamp for coactivator recruitment. However, these analyses have not sufficiently addressed the mechanisms for differential actions of various synthetic steroids in terms of fine tuning of multiple functions of whole receptor molecules. In the present study, we used the glucocorticoid receptor (GR)-specific agonist cortivazol (CVZ) to probe the plasticity and functional modularity of the GR. Structural docking analysis revealed that although CVZ is more bulky than other agonists, it can be accommodated in the ligand binding pocket of the GR by reorientation of several amino acid side chains but without major alterations in the active conformation of the LBD. In this induced fit model, the phenylpyrazole A-ring of CVZ establishes additional contacts with helices 3 and 5 of the LBD that may contribute to a more stable LBD configuration. Structural and functional analysis revealed that CVZ is able to compensate for the deleterious effects of a C-terminal deletion of the LBD in a manner that mimics the stabilizing influence of the F602S point mutation. CVZ-mediated productive recruitment of transcriptional intermediary factor 2 to the C-terminally deleted LBD requires the receptor’s own DNA binding domain and is positively influenced by the N-terminal regions of GR or progesterone receptor. These results support a model where ligand-dependent conformational changes in the LBD play a role in GR-mediated gene regulation via modular interaction with the DBD and activation function-1.
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