European Biophysics Journal

, Volume 39, Issue 11, pp 1471–1475 | Cite as

A canonical cation–π interaction stabilizes the agonist conformation of estrogen-like nuclear receptors

  • Núria Queralt-Rosinach
  • Jordi MestresEmail author
Original Paper


Representative crystal structures of the ligand-binding domain for the majority of nuclear receptors are currently available. A systematic comparative analysis of these structures identified an energetically favorable cation–π interaction that involves an amino acid located at the extreme C-terminal end and appears to form only in the agonist conformation of the estrogen receptor α, glucocorticoid, mineralocorticoid, progesterone, and androgen receptors. It is postulated that this cation–π interaction is used by members of the estrogen-like subfamily to provide additional stabilization to the transcriptional active conformation upon ligand binding.


Protein stability Side-directed mutagenesis Drug design Agonist binding 



Grant sponsor: Spanish Ministerio de Educación y Ciencia and Instituto de Salud Carlos III; Grant number: BIO2008-02329.


  1. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) The Protein Data Bank. Nucleic Acids Res 28:235–242.
  2. Brown TR, Lubahn DB, Wilson EM, French FS, Migeon CJ, Corden JL (1990) Functional characterization of naturally occurring mutant androgen receptors from subjects with complete androgen insensitivity. Mol Endocrinol 4:1759–1772CrossRefPubMedGoogle Scholar
  3. Chen CP, Chern SR, Chen BF, Wang W, Hwu YM (2000) Hamartoma in a pubertal patient with complete androgen insensitivity syndrome and R(831)X mutation of the androgen receptor gene. Fertil Steril 74:182–183CrossRefPubMedGoogle Scholar
  4. Couette B, Jalaguier S, Hellal-Levy C, Lupo B, Fagart J, Auzou G, Rafestin-Oblin ME (1998) Folding requirements of the ligand-binding domain of the human mineralocorticoid receptor. Mol Endocrinol 12:855–863CrossRefPubMedGoogle Scholar
  5. DeLano WL (2005) The case for open-source software in drug discovery. Drug Discov Today 10:213–217. Google Scholar
  6. Dougherty DA (1996) Cation–pi interactions in chemistry and biology: a new view of benzene, Phe, Tyr, and Trp. Science 271:163–168CrossRefPubMedGoogle Scholar
  7. Escriva H, Safi R, Hänni C, Langlois M-C, Saumitou-Laprade P, Sthéhelin D, Capron A, Pierce R, Laudet V (1997) Ligand binding was acquired during evolution of nuclear receptors. Proc Natl Acad Sci USA 94:6803–6808CrossRefPubMedGoogle Scholar
  8. Gallivan JP, Dougherty DA (1999) Cation–π interactions in structural biology. Proc Natl Acad Sci USA 96:9459–9464. Google Scholar
  9. García-Serna R, Opatowski L, Mestres J (2006) FCP: functional coverage of the proteome by structures. Bioinformatics 22:1792–1793. Google Scholar
  10. Gottlieb B, Beitel LK, Wu JH, Trifiro M (2004) The androgen receptor gene mutations database (ARDB): 2004 update. Hum Mutat 23:527–533. Google Scholar
  11. Gronemeyer H, Gustafsson JA, Laudet V (2004) Principles for modulation of the nuclear receptor superfamily. Nat Rev Drug Discov 3:950–964CrossRefPubMedGoogle Scholar
  12. Katzenellenbogen BS, Sun J, Harrington WR, Kraichely DM, Ganessunker D, Katzenellenbogen JA (2001) Structure-function relationships in estrogen receptors and the characterization of novel selective estrogen receptor modulators with unique pharmacological profiles. Ann N Y Acad Sci 949:6–15CrossRefPubMedGoogle Scholar
  13. Kauppi B, Jakob C, Färnegårdh M, Yang J, Ahola H, Alarcon M, Calles K, Engström O, Harlan J, Muchmore S, Ramqvist AK, Thorell S, Ohman L, Greer J, Gustafsson JA, Carlstedt-Duke J, Carlquist M (2003) The three-dimensional structures of antagonistic and agonistic forms of the glucocorticoid receptor ligand-binding domain. J Biol Chem 278:22748–22754CrossRefPubMedGoogle Scholar
  14. Lupyan D, Leo-Macias A, Ortiz AR (2005) A new progressive-iterative algorithm for multiple structure alignment. Bioinformatics 21:3255–3263. Google Scholar
  15. Ma JC, Dougherty DA (1997) The cation–pi interaction. Chem Rev 97:1303–1324CrossRefPubMedGoogle Scholar
  16. Mestres J (2000) Gaussian-based alignment of protein structures: deriving a consensus superposition when alternative solutions exist. J Mol Model 6:539–549CrossRefGoogle Scholar
  17. Moras D, Gronemeyer H (1998) The nuclear receptor ligand-binding domain: structure and function. Curr Opin Cell Biol 10:384–391CrossRefPubMedGoogle Scholar
  18. Prajapati RS, Sirajuddin M, Durani V, Sreeramulu S, Varadarajan R (2006) Contribution of cation–pi interactions to protein stability. Biochemistry 45:15000–15010CrossRefPubMedGoogle Scholar
  19. Radmayr C, Culig Z, Glatzl J, Neuschmid-Kaspar F, Bartsch G, Klocker H (1997) Androgen receptor point mutations as the underlying molecular defect in 2 patients with androgen insensitivity syndrome. J Urol 158:1553–1556CrossRefPubMedGoogle Scholar
  20. Tahiri B, Auzou G, Nicolas JC, Sultan C, Lupo B (2001) Participation of critical residues from the extreme C-terminal end of the human androgen receptor in the ligand binding function. Biochemistry 40:8431–8437CrossRefPubMedGoogle Scholar
  21. Tina KG, Bhadra R, Srinivasan N (2007) PIC: protein interactions calculator. Nucleic Acids Res 35:W473–W476. Google Scholar
  22. van Durme JJJ, Bettler E, Folkertsma S, Horn F, Vriend G (2003) NRMD: nuclear receptor mutation database. Nucleic Acids Res 31:331–333. Google Scholar
  23. Xu EH, Lambert MH (2003) Structural insights into regulation of nuclear receptors by ligands. Nucl Recept Signal 1:e004PubMedGoogle Scholar
  24. Yaegashi N, Uehara S, Senoo M, Sato J, Fujiwara J, Funato T, Sasaki T, Yajima A (1999) Point mutations in the steroid-binding domain of the androgen receptor gene of five Japanese patients with androgen insensitivity syndrome. Tohoku J Exp Med 187:263–272CrossRefPubMedGoogle Scholar

Copyright information

© European Biophysical Societies' Association 2010

Authors and Affiliations

  1. 1.Chemogenomics Laboratory, Research Program on Biomedical Informatics (GRIB)Institut Municipal d’Investigació Mèdica and Universitat Pompeu FabraBarcelonaSpain

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