Glucocorticoids

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Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor. Dexamethasone is a glucocorticoid medication. It is the most potent glucocorticoid and it has not mineralocorticoid potency.

  • Glucocorticoid receptor.
    • Human glucocorticoid receptor ligand-binding domain bound to dexamethasone (1m2z).
    • Glucocorticoid Receptor in complex with budesonide (5nfp).
    • Budesonide binding site. Water molecule is shown as red sphere.
    • Mometasone furoate binding site.
  • Forkhead box proteins (FOX) are transcription factors involved in regulation of gene expression.[1]. FOXO1 activation contributes to glucocorticoid-induced beta cell death[2]. FOX contain a DNA-binding motif (DBD) of 80-100 amino acids having a winged-helix shape.
    • Human FoxO1 DNA-binding domain with DNA, Ca+2 and Cl- ions.
    • Ca coordination site. Water molecules shown as red spheres.
    • Cl coordination site.
  • Nuclear receptor coactivator (NCOA) is a protein recruited by nuclear receptors in order to enhance or repress DNA transcription. NCOA is involved in coactivation with transcription factors[3]. NCOA1 shows histone acetyltransferase activity and is required for steroid hormone response. NCOA2 is a DNA transcription coactivator with glucocorticoid receptor.
    • NCOA/STAT6 transactivator domain LXXLL peptide interactions.
    • 1st Iod coordination site.
    • 2nd Iod coordination site. Water molecules are shown as red spheres.
    • 3th and 4th Iod coordination sites.
    • 5th Iod coordination site.
  • Thioredoxin Reductase (TrxR) is an enzyme which reduces thioredoxin using NADPH[4]. Mutations in TrxR-2 are associated with familial glucocorticoid deficiency[5]. Thioredoxin Reductase (TrxR) is an enzyme which reduces thioredoxin using NADPH[6]. TrxR-2 is mitochondrial. For more details see User:Sarah Abdalla/Thioredoxin Reductase. TrxR and Trx form an intramolecular Cys-Cys bond[7]. FAD binding site. Water molecules are shown as red spheres.
  • Microsomal Prostaglandin E synthase (PGES) converts cyclooxygenase (COX)-derived prostaglandin to PGE2. It is membrane-associated and belongs to the microsomal glutathione S-transferase family. PGES is preferentially linked with the inducible COX-2[8] . PGES is induced by proinflammatory stimuli and down-regulated by anti-inflammatory glucocorticoids[9]. Microsomal Prostaglandin E synthase is membrane-associated (coordinates are from OPM database. The anti-inflammatory inhibitor binds to PGES in a pocket above the glutathione and interacts with various side-chains of a helix[10]. Water molecules are shown as red spheres.


Rat glucocorticoid receptor DNA-binding domain dimer complex with DNA and Zn+2 ions (grey) (PDB entry 3g6r)

Drag the structure with the mouse to rotate

See also:

References

  1. Tuteja G, Kaestner KH. SnapShot: forkhead transcription factors I. Cell. 2007 Sep 21;130(6):1160. PMID:17889656 doi:http://dx.doi.org/10.1016/j.cell.2007.09.005
  2. Kaiser G, Gerst F, Michael D, Berchtold S, Friedrich B, Strutz-Seebohm N, Lang F, Haring HU, Ullrich S. Regulation of forkhead box O1 (FOXO1) by protein kinase B and glucocorticoids: different mechanisms of induction of beta cell death in vitro. Diabetologia. 2013 Jul;56(7):1587-95. doi: 10.1007/s00125-013-2863-7. Epub 2013, Feb 23. PMID:23435785 doi:http://dx.doi.org/10.1007/s00125-013-2863-7
  3. Horwitz KB, Jackson TA, Bain DL, Richer JK, Takimoto GS, Tung L. Nuclear receptor coactivators and corepressors. Mol Endocrinol. 1996 Oct;10(10):1167-77. PMID:9121485 doi:http://dx.doi.org/10.1210/mend.10.10.9121485
  4. Arner ES, Holmgren A. Physiological functions of thioredoxin and thioredoxin reductase. Eur J Biochem. 2000 Oct;267(20):6102-9. PMID:11012661
  5. Prasad R, Chan LF, Hughes CR, Kaski JP, Kowalczyk JC, Savage MO, Peters CJ, Nathwani N, Clark AJ, Storr HL, Metherell LA. Thioredoxin Reductase 2 (TXNRD2) mutation associated with familial glucocorticoid deficiency (FGD). J Clin Endocrinol Metab. 2014 Aug;99(8):E1556-63. doi: 10.1210/jc.2013-3844. Epub, 2014 Mar 6. PMID:24601690 doi:http://dx.doi.org/10.1210/jc.2013-3844
  6. Arner ES, Holmgren A. Physiological functions of thioredoxin and thioredoxin reductase. Eur J Biochem. 2000 Oct;267(20):6102-9. PMID:11012661
  7. Fritz-Wolf K, Kehr S, Stumpf M, Rahlfs S, Becker K. Crystal structure of the human thioredoxin reductase-thioredoxin complex. Nat Commun. 2011 Jul 12;2:383. doi: 10.1038/ncomms1382. PMID:21750537 doi:10.1038/ncomms1382
  8. Murakami M, Nakatani Y, Tanioka T, Kudo I. Prostaglandin E synthase. Prostaglandins Other Lipid Mediat. 2002 Aug;68-69:383-99. PMID:12432931
  9. Kudo I, Murakami M. Prostaglandin E synthase, a terminal enzyme for prostaglandin E2 biosynthesis. J Biochem Mol Biol. 2005 Nov 30;38(6):633-8. PMID:16336776
  10. Luz JG, Antonysamy S, Kuklish SL, Condon B, Lee MR, Allison D, Yu XP, Chandrasekhar S, Backer R, Zhang A, Russell M, Chang SS, Harvey A, Sloan AV, Fisher MJ. Crystal Structures of mPGES-1 Inhibitor Complexes Form a Basis for the Rational Design of Potent Analgesic and Anti-Inflammatory Therapeutics. J Med Chem. 2015 May 20. PMID:25961169 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b00330

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