+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Crystal structure of the T877A human androgen receptor ligand-binding domain complexed to cyproterone acetate provides insight for ligand-induced conformational changes and structure-based drug design



Crystal structure of the T877A human androgen receptor ligand-binding domain complexed to cyproterone acetate provides insight for ligand-induced conformational changes and structure-based drug design



Journal of Biological Chemistry 282(18): 13648-13655



Cyproterone acetate (CPA) is a steroidal antiandrogen used clinically in the treatment of prostate cancer. Compared with steroidal agonists for the androgen receptor (AR) (e.g. dihydrotestosterone, R1881), CPA is bulkier in structure and therefore seemingly incompatible with the binding pockets observed in currently available x-ray crystal structures of the AR ligand-binding domain (LBD). We solved the x-ray crystal structure of the human AR LBD bound to CPA at 1.8A in the T877A variant, a mutation known to increase the agonist activity of CPA and therefore facilitate purification and crystal formation of the receptor.drug complex. The structure demonstrates that bulk from the 17alpha-acetate group of CPA induces movement of the Leu-701 side chain, which results in partial unfolding of the C-terminal end of helix 11 and displacement of the loop between helices 11 and 12 in comparison to all other AR LBD crystal structures published to date. This structural alteration leads to an expansion of the AR binding cavity to include an additional pocket bordered by Leu-701, Leu-704, Ser-778, Met-780, Phe-876, and Leu-880. Further, we found that CPA invokes transcriptional activation in the L701A AR at low nanomolar concentrations similar to the T877A mutant. Analogous mutations in the glucocorticoid receptor (GR) and progesterone receptor were constructed, and we found that CPA was also converted into a potent agonist in the M560A GR. Altogether, these data offer information for structure-based drug design, elucidate flexible regions of the AR LBD, and provide insight as to how CPA antagonizes the AR and GR.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 013675635

Download citation: RISBibTeXText

PMID: 17311914

DOI: 10.1074/jbc.m611711200


Related references

Crystal structure of the peroxisome proliferator-activated receptor gamma (PPARgamma) ligand binding domain complexed with a novel partial agonist: a new region of the hydrophobic pocket could be exploited for drug design. Journal of Medicinal Chemistry 51(24): 7768-7776, 2008

Homology modelling of the nuclear receptors: human oestrogen receptorbeta (hERbeta), the human pregnane-X-receptor (PXR), the Ah receptor (AhR) and the constitutive androstane receptor (CAR) ligand binding domains from the human oestrogen receptor alpha (hERalpha) crystal structure, and the human peroxisome proliferator activated receptor alpha (PPARalpha) ligand binding domain from the human PPARgamma crystal structure. Journal of Steroid Biochemistry and Molecular Biology 84(2-3): 117-132, 2003

Crystal structure of the Vibrio cholerae VqmA-ligand-DNA complex provides insight into ligand-binding mechanisms relevant for drug design. Journal of Biological Chemistry 294(8): 2580-2592, 2019

Homology modelling of the nuclear receptors Human oestrogen receptorbeta , the human pregnane-X-receptor , the Ah receptor and the constitutive androstane receptor ligand binding domains from the human oestrogen receptor alpha crystal structure, and the human peroxisome proliferator activated receptor alpha ligand binding domain from the human PPARgamma crystal structure. Journal of Steroid Biochemistry & Molecular Biology 84(2-3): 117-132, 2003

Vitamin D Analogues with a p-Hydroxyphenyl Group at the C25 Position: Crystal Structure of Vitamin D Receptor Ligand-Binding Domain Complexed with the Ligand Explains the Mechanism Underlying Full Antagonistic Action. Journal of Medicinal Chemistry 60(20): 8394-8406, 2017

Comparison of crystal structures of human androgen receptor ligand-binding domain complexed with various agonists reveals molecular determinants responsible for binding affinity. Protein Science 15(5): 987-999, 2006

Crystallographic structures of the ligand-binding domains of the androgen receptor and its T877A mutant complexed with the natural agonist dihydrotestosterone. Proceedings of the National Academy of Sciences of the United States of America 98(9): 4904-4909, 2001

Rational structure-based drug design and optimization in the ligand-binding domain of the glucocorticoid receptor-α. Future Medicinal Chemistry 1(2): 345-359, 2009

Crystal structure of human lectin-like, oxidized low-density lipoprotein receptor 1 ligand binding domain and its ligand recognition mode to OxLDL. Structure 13(6): 905-917, 2005

Structural characterization of the human androgen receptor ligand-binding domain complexed with EM5744, a rationally designed steroidal ligand bearing a bulky chain directed toward helix 12. Journal of Biological Chemistry 282(42): 30910-9, 2007

The 2.0 A crystal structure of the ERalpha ligand-binding domain complexed with lasofoxifene. Protein Science 16(5): 897-905, 2007

The three-dimensional structure of the ligand-binding domain of a wild-type bacterial chemotaxis receptor. Structural comparison to the cross-linked mutant forms and conformational changes upon ligand binding. Journal of Biological Chemistry 268(13): 9787-9792, 1993

Evidence for Ligand-independent Transcriptional Activation of the Human Estrogen-related Receptor a (ERRa). Crystal Structure of ERRa Ligand Binding Domain in Complex with Peroxisome Proliferator-activated Receptor Coactivor-1a. Journal of Biological Chemistry 279(47): 330-7, 2004

Crystal structure of Abl-SH3 domain complexed with a designed high-affinity peptide ligand: implications for SH3-ligand interactions. Journal of Molecular Biology 281(3): 3-21, 1998

Crystal structure of the abl-SH3 domain complexed with a designed high-affinity peptide ligand: implications for SH3-ligand interactions. Journal of Molecular Biology 281(3): 513-521, 1998