Modelling the glucocorticoid receptor and producing therapeutic agents with anti-inflammatory effects but reduced side-effects
Glucocorticoid hormones exert a wide spectrum of metabolic and immunological effects. They are synthesized from a cholesterol precursor and are structurally related to the other steroid hormones, progesterone, aldosterone and oestrogen. They act through the glucocorticoid receptor (GR), a member of...
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Published in | Experimental physiology Vol. 92; no. 2; pp. 299 - 309 |
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Main Authors | , |
Format | Journal Article |
Language | English |
Published |
Oxford, UK
The Physiological Society
01.03.2007
Blackwell Publishing Ltd |
Subjects | |
Online Access | Get full text |
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Summary: | Glucocorticoid hormones exert a wide spectrum of metabolic and immunological effects. They are synthesized from a cholesterol
precursor and are structurally related to the other steroid hormones, progesterone, aldosterone and oestrogen. They act through
the glucocorticoid receptor (GR), a member of the nuclear receptor superfamily. The GR is an intracellular receptor; the hydrophobic
ligand accesses its receptor by diffusion across the plasma membrane. The ligand-activated GR translocates to the nucleus
to regulate expression of its target genes. The GR, in common with the rest of the receptor family, can be functionally divided
into an N-terminal transcription activation domain, a central DNA binding domain and a C-terminal ligand binding domain, which
also includes a second transactivation domain. Although synthetic glucocorticoids are the most potent anti-inflammatory agents
known, their use is limited owing to the range and severity of their side-effects. The structure of the ligand binding domain
of the glucocorticoid receptor has now been solved, and a series of studies has shown that even subtle changes to the ligand
structure alter the final conformation of the ligandâreceptor complex, with consequences for further protein recruitment and
for the function of the receptor. This, coupled with the successful development of selective oestrogen receptor agonists,
has led to concerted efforts to find selective GR ligands, with preserved beneficial anti-inflammatory activity, but reduced
side-effect profile. Current efforts have identified several useful tool compounds, and further molecules are in development
in several pharmaceutical companies. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-3 ObjectType-Review-1 |
ISSN: | 0958-0670 1469-445X |
DOI: | 10.1113/expphysiol.2006.036194 |