PMID- 24225022 OWN - NLM STAT- MEDLINE DCOM- 20140218 LR - 20191210 IS - 1521-0111 (Electronic) IS - 0026-895X (Linking) VI - 85 IP - 2 DP - 2014 Feb TI - A structural explanation of the effects of dissociated glucocorticoids on glucocorticoid receptor transactivation. PG - 226-36 LID - 10.1124/mol.113.085860 [doi] AB - There is a therapeutic need for glucocorticoid receptor (GR) ligands that distinguish between the transrepression and transactivation activity of the GR, the later thought to be responsible for side effects. These ligands are known as "dissociated glucocorticoids" (dGCs). The first published dGCs, RU24782 (9alpha-fluoro-11beta-hydroxy-16alpha-methylpregna-21-thiomethyl-1,4-diene-3,20-dione) and RU24858 (9alpha-fluoro-11beta-hydroxy-16alpha-methylpregna-21-cyanide-1,4-diene-3,20-dione), do not have the 17alpha-hydroxyl group that characterizes dexamethasone (Dex; 9alpha-fluoro-11beta,17alpha,21-trihydroxy-16alpha-methylpregna-1,4-diene-3,20-dione), and they differ from one another by having C21-thiomethyl and C21-cyanide moieties, respectively. Our aim was therefore to establish the structural basis of their activity. Both RU24782 and RU24858 induced a transactivation activity highly dependent on the GR expression level but always lower than dexamethasone. They also display less ability than dexamethasone to trigger steroid receptor coactivator 1 (SRC-1) recruitment and histone H3 acetylation. Docking studies, validated by mutagenesis experiments, revealed that dGCs are not anchored by Gln642, in contrast to Dex, which is hydrogen bonded to this residue via its 17alpha-hydroxyl group. This contact is essential for SRC-1 recruitment and subsequent dexamethasone-induced GR transactivation, but not transrepression. The ability of dGCs to make contacts with Ile747, for both RU24858 and RU24782 and with Asn564 for RU24858 are not strong enough to maintain GR in a conformation able to efficiently recruit SRC-1, unless SRC-1 is overexpressed. Overall, our findings provide some structural guidelines for the synthesis of potential new dissociated glucocorticoids with a better therapeutic ratio. FAU - Dezitter, Xavier AU - Dezitter X AD - Institut National de la Sante et de la Recherche Medicale U837, Institut de Recherche pour le Cancer de Lille, Lille, France (X.D., S.T., B.M., D.H., P.F., T.I.); Institut National de la Sante et de la Recherche Medicale U773, Centre de Recherche Biomedicale Bichat-Beaujon, CRB3 (J.F., M.F., M.-E.R.-O.); and Universite Paris 7- Denis Diderot, site Bichat, Paris, France (J.F., M.F., M.-E.R.-O.). FAU - Fagart, Jerome AU - Fagart J FAU - Taront, Solenne AU - Taront S FAU - Fay, Michel AU - Fay M FAU - Masselot, Bernadette AU - Masselot B FAU - Hetuin, Dominique AU - Hetuin D FAU - Formstecher, Pierre AU - Formstecher P FAU - Rafestin-Oblin, Marie-Edith AU - Rafestin-Oblin ME FAU - Idziorek, Thierry AU - Idziorek T LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20131113 PL - United States TA - Mol Pharmacol JT - Molecular pharmacology JID - 0035623 RN - 0 (Glucocorticoids) RN - 0 (Receptors, Glucocorticoid) RN - 0 (TSC22D3 protein, human) RN - 0 (Transcription Factors) RN - 7S5I7G3JQL (Dexamethasone) RN - EC 2.3.1.48 (Nuclear Receptor Coactivator 1) SB - IM MH - Active Transport, Cell Nucleus MH - Animals MH - Binding Sites MH - COS Cells MH - Cells, Cultured MH - Chlorocebus aethiops MH - Dexamethasone/pharmacology MH - Glucocorticoids/chemistry/metabolism/*pharmacology MH - Humans MH - Nuclear Receptor Coactivator 1/physiology MH - Promoter Regions, Genetic MH - Protein Conformation MH - Receptors, Glucocorticoid/chemistry/*genetics/metabolism MH - Transcription Factors/genetics MH - Transcriptional Activation/*drug effects EDAT- 2013/11/15 06:00 MHDA- 2014/02/19 06:00 CRDT- 2013/11/15 06:00 PHST- 2013/11/15 06:00 [entrez] PHST- 2013/11/15 06:00 [pubmed] PHST- 2014/02/19 06:00 [medline] AID - mol.113.085860 [pii] AID - 10.1124/mol.113.085860 [doi] PST - ppublish SO - Mol Pharmacol. 2014 Feb;85(2):226-36. doi: 10.1124/mol.113.085860. Epub 2013 Nov 13.