Structure and Function of the Glucocorticoid Receptor DNA-Binding Domain

Implications for the Steroid/Nuclear Receptor Superfamily
  • B. Luisi
  • W. Xu
  • P. Sigler
Part of the Nucleic Acids and Molecular Biology book series (NUCLEIC, volume 7)


Steroids and other lipophilic hormones affect gene expression via specialized receptor proteins that reside in the cytoplasm or cell nucleus. Some features of this mechanism are illustrated by the well-characterized example of the glucocorticoid receptor: on binding the hormone, the receptor translocates from the cytoplasm to the nucleus, where it associates with particular sites in the genome and affects transcription rates of target genes. To date, some 30 distinct receptors sharing certain functional similarities with the glucocorticoid receptor have been identified. This closely related group has been termed the “steroid/nuclear receptor superfamily”, and members have been discovered in species as diverse as arthropods and mammals, representing some 500 million years of evolutionary divergence (Beato 1989; Parker 1991; Seagraves 1991; Laudet et al. 1992). The glucocorticoid receptor has been one of the more extensively studied members of the superfamily and has provided insight into the function of the steroid/nuclear receptors.


Retinoic Acid Glucocorticoid Receptor Nuclear Receptor Major Groove Base Contact 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Alroy I, Freedman LP (1992) DNA binding analysis of glucocorticoid specificity mutants. Nuclic Acids Res 20: 1045–1052CrossRefGoogle Scholar
  2. Baleja JD, Marmorstein R, Harrison SC, Wagner G (1992) Solution structure of the DNA-binding domain of Cd2-GAL4 from S. cerevisiae. Nature 356: 450–453PubMedCrossRefGoogle Scholar
  3. Beato M (1989) Gene regulation by steroid hormones. Cell 56: 335–344PubMedCrossRefGoogle Scholar
  4. Berg JM (1988) Proposed structure for the zinc-binding domains from transcription factor IIIA and related proteins. Proc Natl Acad Sci USA 85: 99–102PubMedCrossRefGoogle Scholar
  5. Bugge TH, Pohl J, Lonnoy O, Stunnenberg H (1992) RXRa, a promiscuous partner of retinoic acid and thyroid hormone receptors. EMBO J 11: 1409–1417PubMedGoogle Scholar
  6. Dahlman-Wright K, Siltata-Ross H, Carstedt-Duke J, Gustafsson J-A (1990) Protein- protein interactions facilitate DNA binding by the glucocorticoid receptor DNA binding domain. J Biol Chem 265: 14030–14035PubMedGoogle Scholar
  7. Dahlman-Wright K, Wright A, Gustafsson J-A, Carstedt-Duke J (1991) Interaction of the glucocorticoid receptor DNA-binding domain with DNA is mediated by a short segment of five amino acids. J Biol Chem 266: 3107–3112PubMedGoogle Scholar
  8. Danielson M, Hinck L, Ringold GM (1989) Two amino acids within the knuckle of the first zinc finger specify response element activation by the glucocorticoid receptor. Cell 57: 1131–1138CrossRefGoogle Scholar
  9. Drew HR, McCall MJ, Calladine CR (1988) Recent studies of DNA in the crystal. Annu Rev Cell Biol 4: 1–20PubMedCrossRefGoogle Scholar
  10. Dreyer C, Krey G, Keller H, Givel F, Helftenbein G, Wahli W (1992) Control of the peroxisomal β-oxidation pathway by a novel family of nuclear hormone receptors. Cell: 68: 879–887PubMedCrossRefGoogle Scholar
  11. Farwell SE, Lees JA, White R, Parker MG (1990) Characterization and localization of steroid binding and dimerization activities in the mouse estrogen receptor. Cell 60: 953–962CrossRefGoogle Scholar
  12. Forman BM, Samuels HH (1990) Interactions among a subfamily of nuclear hormone receptors: the regulatory zipper model. Mol Endocrinol 90: 1293–1301CrossRefGoogle Scholar
  13. Freedman LP, Luisi BF (1993) On the mechanism of DNA binding by nuclear hormone receptors: a structural and functional perspective. J Cell Biochem 51: 140–150PubMedCrossRefGoogle Scholar
  14. Freedman LP, Towers T (1991) DNA binding properties of the vitamin D3 receptor zinc finger region. Mol Endocrinol 5 (12): 1815–1826PubMedCrossRefGoogle Scholar
  15. Freedman LP, Luisi BF, Korszun ZR, Basavappa R, Sigler PB, Yamamoto KR (1988a) The function and structure of the metal coordination sites within the gucocorticoid receptor DNA binding domain. Nature 334: 543–546PubMedCrossRefGoogle Scholar
  16. Freedman LP, Yamamoto KR, Luisi BF, Sigler PB (1988b) More fingers in hand. Cell 54: 444PubMedCrossRefGoogle Scholar
  17. Freedman LP, Yoshinaga SK, Vanderbilt JN, Yamamoto KR (1989) In vitro transcription enhancement by purified derivatives of the glucocorticoid receptor. Science 245: 298–301PubMedCrossRefGoogle Scholar
  18. Green S, Kumar V, Theulaz I, Whali W, Chambon P (1988) The N-terminal DNA binding zinc finger of the oestrogen and glucocorticoid receptors determines target gene specificity. EMBO J 7: 3037–3044PubMedGoogle Scholar
  19. Hard T, Kellenbach E, Boelens R, Maler BA, Dahlman K, Freedman LP, Carlstedt-Duke J, Yamamoto KR, Gustafsson JA, Kaptein R (1990a) Solution structure of the glucocorticoid receptor DNA binding domain. Science 249: 157–160PubMedCrossRefGoogle Scholar
  20. Hard T, Dahlman K, Carstedt-Duke J, Gustafsson J-A, Rigler R (1990b) Cooperativity and specificity in the interactions between DNA and the glucocorticoid receptor DNA- binding domain. Biochemistry 29: 5358–5364PubMedCrossRefGoogle Scholar
  21. Hughes MR, Malloy PJ, Kieback DG, Kesterson RA, Pike JW, Feldman D, O’Malley BW (1989) Point mutations in the human vitamin D receptor gene associated with hypocalcemic rickets. Science 242: 1702–1705CrossRefGoogle Scholar
  22. Issemann I, Green S (1990) Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 347: 645–650PubMedCrossRefGoogle Scholar
  23. Kim B, Little JW (1992) Dimerization of a specific DNA-binding protein on the DNA. Nature 255: 203–206Google Scholar
  24. Klevit RE, Herriott JR, Horvath SJ (1990) Solution structure of a zinc finger domain of yeast ADR1. Proteins 7: 215–226PubMedCrossRefGoogle Scholar
  25. Kliewer SA, Umesono K, Mangelsdorf DJ, Evans RM (1992) Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone, and vitamin D3 signalling. Nature 355: 446–449PubMedCrossRefGoogle Scholar
  26. Kraulis PJ (1991) MOLSCRIPT: a program to produce both detailed and schematic plots of protein structures. J Appl Crystallogr 24: 946–950CrossRefGoogle Scholar
  27. Kraulis PJ, Raine ARC, Gadhavi PL, Laue ED (1992) Structure of the DNA-binding domain of zinc GAL4. Nature 356: 448–450PubMedCrossRefGoogle Scholar
  28. Kumar V, Chambon P (1988) The estrogen receptor binds tighly to its responsive element as a ligand-induced homodimer. Cell 55: 145–156PubMedCrossRefGoogle Scholar
  29. Laudet V, Hanni C, Coll J, Catzfiis F, Stehelin D (1992) Evolution of the nuclear receptor gene superfamily. EMBO J 11: 1003–1013PubMedGoogle Scholar
  30. Lee MS, Gippert GP, Soman KV, Case DA, Wright PE (1989) Three-dimensional solution structure of a single zinc finger DNA-binding domain. Science 245: 635–637PubMedCrossRefGoogle Scholar
  31. Leid M, Kastner P, Lyons R, Nakshatri H, Saunders M, Zacharewski T, Chen J-A, Staub A, Gamier J-M, Mader S, Chambon P (1992) Purification, cloning, and RXR identity of the HeLa cell factor with which RAR or TR heterodimerizes to bind target sequences. Cell 68: 37–395CrossRefGoogle Scholar
  32. Luisi BF, Sigler PB (1990) The stereochemistry and biochemistry of the trp repressor-operator complex. Biochim Biophys Acta 1048: 113–126PubMedGoogle Scholar
  33. Luisi BF, Xu WX, Otwinowski Z, Freedman LP, Yamamoto KR, Sigler PB (1991) Crystallographic analysis of the interaction of the glucocorticoid receptor with DNA. Nature 352: 497–505PubMedCrossRefGoogle Scholar
  34. Mader S, Kumar V, de Vereneuil H, Chambon P (1989) Three amino acids of the oestrogen receptor are essential to its ability to distinguish an oestrogen from a glucocorticoid-responsive element. Nature 338: 271–274PubMedCrossRefGoogle Scholar
  35. Marks MS, Hallenbeck PL, Nagata T, Segars JH, Appella E, Nikode VM, Ozato K (1992) H-2RIIBP (RXRb) heterodimerization provides a mechanism for combinatorial diversity in the regulation of retinoic acid and thyroid hormone responsive genes. EMBO J 11: 1419–1435PubMedGoogle Scholar
  36. Marmorstein R, Carey M, Ptashne M, Harrison SC (1992) DNA recognition by GAL4: structure of a protein-DNA complex. Nature 356: 408–414PubMedCrossRefGoogle Scholar
  37. Miller J, McLachlan AD, Klug A (1985) Repetitive zinc-binding domains in the protein transcription factor IIIA from Xenopus ocytes. EMBO J 4: 1609–1614PubMedGoogle Scholar
  38. Morellet N, Jullian N, De Rocquigny H, Maigret B, Darlix J-L, Roques BP (1992) Determination of the structure of the nucleocapsid protein NCp7 from the human immunodeficiency virus type 1 by JH NMR. EMBO J 11: 3059–3065PubMedGoogle Scholar
  39. Nordeen SK, Suh BJ, Kuhnel B, Hutchison CA (1990) Structural determinants of a glucocorticoid receptor recognition element. Mol Endocrinol 4: 1866–1873PubMedCrossRefGoogle Scholar
  40. Otwinowski Z, Schevitz RW, Zhang R-G, Lawson CL, Joachimiak A, Marmorstein RQ, Luisi BF, Sigler PB (1988) Crystal structure of trp repressor/operator complex at atomic resolution. Nature 335: 321–329PubMedCrossRefGoogle Scholar
  41. Parker MG (1991) Nuclear hormone receptors. Academic Press, LondonCrossRefGoogle Scholar
  42. Patel L, Abate C, Curran T (1990) Altered protein conformation on DNA binding by Fos and Jun. Nature 347:572–575Google Scholar
  43. Pavletich NP, Pabo CO (1991) Zinc finger-DNA recognition: crystal structure of a Zif268-DNA complex at 2.1 A. Science 252: 809–817Google Scholar
  44. Perutz MF (1990) Mechanism of cooperativity and allosteric regulation in proteins. Cambridge University Press, CambridgeGoogle Scholar
  45. Rhodes D, Klug A (1980) Helical periodicity of DNA determined by enzyme digestion. Nature 286: 573–578PubMedCrossRefGoogle Scholar
  46. Rut AR, Hewison M, Kristjansson K, Luisi B, O’Riordan JLH, Hughes MR (1993) Mutations in the vitamin D receptor gene and their stereochemical consequences, (submitted)Google Scholar
  47. Schena M, Yamamoto KR (1988) Mammalian glucocorticoid receptor derivatives enhance transcription in yeast. Science 241: 965–967PubMedCrossRefGoogle Scholar
  48. Schena M, Freedman LP, Yamamoto KR (1989) Mutations in the glucocorticoid receptor zinc finger region that distinguish interdigitated DNA binding and transcriptional enhancement activities. Genes Dev 3: 1590–1601PubMedCrossRefGoogle Scholar
  49. Schwabe JWR, Neuhaus D, Rhodes D (1990) Solution structure of the DNA binding domain of the oestrogen receptor. Nature 348: 458–461PubMedCrossRefGoogle Scholar
  50. Seagraves WA (1991) Something old, some things new: the steroid receptor superfamily in Drosophila. Cell 67: 225–228CrossRefGoogle Scholar
  51. Sone T, Marx SJ, Liberman UA, Pike J (1990) A unique point mutation in human vitamin D receptor chromosomal gene confers hereditary resistance of 1,25- dihydroxyvitamin D3. Mol Endocrinol 4: 623–631PubMedCrossRefGoogle Scholar
  52. Sone T, Kerner SA, Saijo T, Takeda E, Pike JW (1991) Mutations in the DNA binding domain of the vitamin D receptor associated with hereditary resistance of 1,25- dihydroxyvitamin D3. In: Norman AW, Bouillon R, Thomasset M (eds) Vitamin D: gene regulation, structure-function analysis, and clinical applications. De Gruyter, New York, pp 84–85Google Scholar
  53. Summers MF, South TL, Kim B, Hare DS (1991) High resolution structure of an HIV zinc fingerlike domain via a new NMR-based distance geometry approach. Biochemistry 29: 329–340CrossRefGoogle Scholar
  54. Towers T, Luisi BF, Asianov A, Freedman LP (1993) DNA target selectivity by the vitamin D3 receptor; Mechanism of dimer binding to an asymmetric repeat element. Proc Natl Acad Sci USA (in press)Google Scholar
  55. Truss M, Chalepakis G, Beato M (1990) Contacts between steroid hormone receptors and thymines in DNA: an interference method. Proc Natl Acad Sci USA 87: 7180–7184PubMedCrossRefGoogle Scholar
  56. Umesono K, Evans RM (1989) Determinants of target gene specificity for steroid/thyroid hormone receptors. Cell 57: 1139–1146PubMedCrossRefGoogle Scholar
  57. Umesono K, Murakami KK, Thompson CC, Evans RM (1991) Direct repeats as selective response elements for the thyroid hormone, retinoic acid, and vitamin D3 receptors. Cell 65: 1255–1266PubMedCrossRefGoogle Scholar
  58. Wilson TE, Paulsen RE, Padgett KA, Milbrant J (1992) Participation of non-zinc finger residues in DNA binding by two nuclear orphan receptors. Science 256: 107–110PubMedCrossRefGoogle Scholar
  59. Wrange O, Eriksson P, Perlmann T (1989) The purified activated glucocorticoid receptor is a homodimer. J Biol Chem 264: 5253–5259PubMedGoogle Scholar
  60. Yu VC, Delsert C, Andersen B, Holloway JM, Devary OV, Naar AM, Kim SY, Boutin J-M, Glass CK, Rosenfeld MG (1991) RXRb: a coregulator that enhances binding of retinoic acid, thyroid hormone and vitamin D receptors to their cognate response elements. Cell 67: 1251–1266PubMedCrossRefGoogle Scholar
  61. Zhang X-K, Hoffmann B, Tran PB-V, Graupner G, Pfahl M (1992) Retinoid X receptor is an auxiliary protein for thyroid hormone and retinoic acid receptors. Nature 355: 441–446PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1993

Authors and Affiliations

  • B. Luisi
    • 1
  • W. Xu
    • 2
  • P. Sigler
    • 2
  1. 1.MRC Virology UnitGlasgowUK
  2. 2.Department of Molecular Biophysics and BiochemistryYale UniversityNew HavenUSA

Personalised recommendations