+ 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

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



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



Antiandrogens are commonly used to treat androgen-dependent disorders. The currently used drugs unfortunately possess very weak affinity for the human AR (hAR), thus indicating the need to develop new high-affinity steroidal antiandrogens. Our compounds are specially designed to impede repositioning of the mobile carboxyl-terminal helix 12, which blocks the ligand-dependent transactivation function (AF-2) located in the AR ligand-binding domain (ARLBD). Using crystal structures of the hARLBD, we first found that H12 could be directly reached from the ligand-binding pocket (LBP) by a chain positioned on the C18 atom of an androgen steroid nucleus. A set of 5alpha-dihydrotestosterone-derived molecules bearing various C18 chains were thus synthesized and tested for their capacity to bind hAR and act as antagonists. Although most of those having very high affinity for hAR were agonists, several very potent antagonists were obtained, confirming the structural importance of the C18 chain. To understand the role of the C18 chain in their agonistic/antagonistic properties, the structure of the hARLBD complexed with one of these agonists, EM5744, was determined at a 1.65-A resolution. We have identified new interactions involving Gln(738), Met(742), and His(874) that explain both the high affinity of this compound and the inability of its bulky chain to prevent the repositioning of H12. This structural information will be helpful to refine the structure of the chains placed on the C18 atom to obtain efficient H12-directed steroidal antiandrogens.

Please choose payment method:






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

Accession: 017140596

Download citation: RISBibTeXText

PMID: 17711855

DOI: 10.1074/jbc.m705524200


Related references

Androgen receptor mutations causing human androgen insensitivity syndromes show a key role of residue M807 in Helix 8-Helix 10 interactions and in receptor ligand-binding domain stability. Molecular Human Reproduction 8(2): 101-108, 2002

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, 2007

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

Homology modelling of the ligand binding domain of mineralocorticoid receptor: close structural kinship with glucocorticoid receptor ligand binding domain and their similar binding mode with DOC (de-oxy corticosterone). Journal of Biomolecular Structure and Dynamics 20(1): 21-29, 2002

Structural evidence for ligand specificity in the binding domain of the human androgen receptor. Implications for pathogenic gene mutations. Journal of Biological Chemistry 275(34): 26164-26171, 2000

An androgen receptor mutation in the direct vicinity of the proposed C-terminal alpha-helix of the ligand binding domain containing the AF-2 transcriptional activating function core is associated with complete androgen insensitivity. Molecular and Cellular Endocrinology 148(1-2): 47-53, 1999

Mass spectrometric characterization of the human androgen receptor ligand-binding domain expressed in Escherichia coli. Biochemistry (American Chemical Society) 40(36): 756-63, 2001

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

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

A Natural Mutation in Helix 5 of the Ligand Binding Domain of Glucocorticoid Receptor Enhances Receptor-Ligand Interaction. Plos one 11(10): E0164628, 2016

Azoospermia associated with a mutation in the ligand-binding domain of an androgen receptor displaying normal ligand binding, but defective trans-activation. Journal of Clinical Endocrinology and Metabolism 83(12): 4303-4309, 1998

Azoospermia associated with a mutation in the ligand-binding domain of an androgen receptor displaying and normal ligand binding, but defective trans-activation. Journal of Clinical Endocrinology and Metabolism 83(12): 4303-4309, 1998

A ligand-entry surface of the nuclear receptor superfamily consists of the helix H3 of the ligand-binding domain. Journal of Molecular Graphics and Modelling 62: 262-275, 2015

A Structural Switch between Agonist and Antagonist Bound Conformations for a Ligand-Optimized Model of the Human Aryl Hydrocarbon Receptor Ligand Binding Domain. Biology 3(4): 645-669, 2014