A canonical cation–π interaction stabilizes the agonist conformation of estrogen-like nuclear receptors
- 106 Downloads
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.
KeywordsProtein 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.
- 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/
- 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
- 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