Skip to main content

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


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.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2


  • 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.

  • 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 4:1759–1772

    CAS  Article  PubMed  Google Scholar 

  • 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 74:182–183

    CAS  Article  PubMed  Google Scholar 

  • 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 12:855–863

    CAS  Article  PubMed  Google Scholar 

  • DeLano WL (2005) The case for open-source software in drug discovery. Drug Discov Today 10:213–217.

    Google Scholar 

  • Dougherty DA (1996) Cation–pi interactions in chemistry and biology: a new view of benzene, Phe, Tyr, and Trp. Science 271:163–168

    CAS  Article  PubMed  Google Scholar 

  • 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 94:6803–6808

    CAS  Article  PubMed  Google Scholar 

  • Gallivan JP, Dougherty DA (1999) Cation–π interactions in structural biology. Proc Natl Acad Sci USA 96:9459–9464.

    Google Scholar 

  • García-Serna R, Opatowski L, Mestres J (2006) FCP: functional coverage of the proteome by structures. Bioinformatics 22:1792–1793.

    Google Scholar 

  • 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 

  • Gronemeyer H, Gustafsson JA, Laudet V (2004) Principles for modulation of the nuclear receptor superfamily. Nat Rev Drug Discov 3:950–964

    CAS  Article  PubMed  Google Scholar 

  • 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 949:6–15

    CAS  Article  PubMed  Google Scholar 

  • 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 278:22748–22754

    CAS  Article  PubMed  Google Scholar 

  • Lupyan D, Leo-Macias A, Ortiz AR (2005) A new progressive-iterative algorithm for multiple structure alignment. Bioinformatics 21:3255–3263.

    Google Scholar 

  • Ma JC, Dougherty DA (1997) The cation–pi interaction. Chem Rev 97:1303–1324

    CAS  Article  PubMed  Google Scholar 

  • Mestres J (2000) Gaussian-based alignment of protein structures: deriving a consensus superposition when alternative solutions exist. J Mol Model 6:539–549

    CAS  Article  Google Scholar 

  • Moras D, Gronemeyer H (1998) The nuclear receptor ligand-binding domain: structure and function. Curr Opin Cell Biol 10:384–391

    CAS  Article  PubMed  Google Scholar 

  • Prajapati RS, Sirajuddin M, Durani V, Sreeramulu S, Varadarajan R (2006) Contribution of cation–pi interactions to protein stability. Biochemistry 45:15000–15010

    CAS  Article  PubMed  Google Scholar 

  • 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 158:1553–1556

    CAS  Article  PubMed  Google Scholar 

  • 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 40:8431–8437

    CAS  Article  PubMed  Google Scholar 

  • Tina KG, Bhadra R, Srinivasan N (2007) PIC: protein interactions calculator. Nucleic Acids Res 35:W473–W476.

    Google Scholar 

  • 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 

  • Xu EH, Lambert MH (2003) Structural insights into regulation of nuclear receptors by ligands. Nucl Recept Signal 1:e004

    PubMed  Google Scholar 

  • 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 187:263–272

    CAS  Article  PubMed  Google Scholar 

Download references


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

Author information

Authors and Affiliations


Corresponding author

Correspondence to Jordi Mestres.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Queralt-Rosinach, N., Mestres, J. A canonical cation–π interaction stabilizes the agonist conformation of estrogen-like nuclear receptors. Eur Biophys J 39, 1471–1475 (2010).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


  • Protein stability
  • Side-directed mutagenesis
  • Drug design
  • Agonist binding