Abstract
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.
Similar content being viewed by others
References
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. http://www.rcsb.org/
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
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
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
DeLano WL (2005) The case for open-source software in drug discovery. Drug Discov Today 10:213–217. http://www.pymol.org/
Dougherty DA (1996) Cation–pi interactions in chemistry and biology: a new view of benzene, Phe, Tyr, and Trp. Science 271:163–168
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
Gallivan JP, Dougherty DA (1999) Cation–π interactions in structural biology. Proc Natl Acad Sci USA 96:9459–9464. http://capture.caltech.edu/
García-Serna R, Opatowski L, Mestres J (2006) FCP: functional coverage of the proteome by structures. Bioinformatics 22:1792–1793. http://cgl.imim.es/fcp/
Gottlieb B, Beitel LK, Wu JH, Trifiro M (2004) The androgen receptor gene mutations database (ARDB): 2004 update. Hum Mutat 23:527–533. http://androgendb.mcgill.ca/
Gronemeyer H, Gustafsson JA, Laudet V (2004) Principles for modulation of the nuclear receptor superfamily. Nat Rev Drug Discov 3:950–964
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
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
Lupyan D, Leo-Macias A, Ortiz AR (2005) A new progressive-iterative algorithm for multiple structure alignment. Bioinformatics 21:3255–3263. http://ub.cbm.uam.es/mammoth/mult/
Ma JC, Dougherty DA (1997) The cation–pi interaction. Chem Rev 97:1303–1324
Mestres J (2000) Gaussian-based alignment of protein structures: deriving a consensus superposition when alternative solutions exist. J Mol Model 6:539–549
Moras D, Gronemeyer H (1998) The nuclear receptor ligand-binding domain: structure and function. Curr Opin Cell Biol 10:384–391
Prajapati RS, Sirajuddin M, Durani V, Sreeramulu S, Varadarajan R (2006) Contribution of cation–pi interactions to protein stability. Biochemistry 45:15000–15010
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
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
Tina KG, Bhadra R, Srinivasan N (2007) PIC: protein interactions calculator. Nucleic Acids Res 35:W473–W476. http://crick.mbu.iisc.ernet.in/~PIC/
van Durme JJJ, Bettler E, Folkertsma S, Horn F, Vriend G (2003) NRMD: nuclear receptor mutation database. Nucleic Acids Res 31:331–333. http://www.receptors.org/NR/
Xu EH, Lambert MH (2003) Structural insights into regulation of nuclear receptors by ligands. Nucl Recept Signal 1:e004
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
Acknowledgments
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
Rights 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). https://doi.org/10.1007/s00249-010-0602-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00249-010-0602-2