3k22
From Proteopedia
Glucocorticoid Receptor with Bound alaninamide 10 with TIF2 peptide
Structural highlights
Disease[GCR_HUMAN] Defects in NR3C1 are a cause of glucocorticoid resistance (GCRES) [MIM:138040]; also known as cortisol resistance. It is a hypertensive, hyperandrogenic disorder characterized by increased serum cortisol concentrations. Inheritance is autosomal dominant.[1] [2] [3] [4] [5] Function[GCR_HUMAN] Receptor for glucocorticoids (GC). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modulator of other transcription factors. Affects inflammatory responses, cellular proliferation and differentiation in target tissues. Could act as a coactivator for STAT5-dependent transcription upon growth hormone (GH) stimulation and could reveal an essential role of hepatic GR in the control of body growth. Involved in chromatin remodeling. Plays a significant role in transactivation.[6] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedCrystallography and computer modeling have been used to exploit a previously unexplored channel in the glucocorticoid receptor (GR). Highly potent, nonsteroidal indazole amides showing excellent complementarity to the channel were designed with the assistance of the computational technique AlleGrow. The accuracy of the design process was demonstrated through crystallographic structural determination of the GR ligand-binding domain-agonist complex of the D-prolinamide derivative 11. The utility of the channel was further exemplified through the design of a potent phenylindazole in which structural motifs, seen to interact with the traditional GR ligand pocket, were abandoned and replaced by interactions within the new channel. Occupation of the channel was confirmed with a second GR crystal structure of this truncated D-alaninamide derivative 13. Compound 11 displays properties compatible with development as an intranasal solution formulation, whereas oral bioavailability has been demonstrated with a related truncated exemplar 14. Data with the pyrrolidinone amide 12 demonstrate the potential for further elaboration within the "meta" channel to deliver compounds with selectivity for the desired transrepressive activity of glucocorticoids. The discovery of these interactions with this important receptor offers significant opportunities for the design of novel GR modulators. Design and x-ray crystal structures of high-potency nonsteroidal glucocorticoid agonists exploiting a novel binding site on the receptor.,Biggadike K, Bledsoe RK, Coe DM, Cooper TW, House D, Iannone MA, Macdonald SJ, Madauss KP, McLay IM, Shipley TJ, Taylor SJ, Tran TB, Uings IJ, Weller V, Williams SP Proc Natl Acad Sci U S A. 2009 Oct 12. PMID:19822747[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Human | Biggadike, K B | Bledsoe, R K | Madauss, K P | McLay, I M | Williams, S P | Alpha helical sandwich | Alternative initiation | Chromatin regulator | Disease mutation | Dna-binding | Glucocorticoid receptor | Glucocorticoid | Gr | Isopeptide bond | Lipid-binding | Meta-channel | Metal-binding | Nuclear receptor | Nucleus | Phosphoprotein | Pseudohermaphroditism | Receptor | Steroid hormone receptor | Steroid-binding | Transcription | Transcription regulation | Zinc-finger
