Differential presentation of protein interaction surfaces on the androgen receptor defines the pharmacological actions of bound ligands.
The pharmacological activity of different nuclear receptor ligands is reflected by their impact on receptor structure. Thus, we asked whether differential presentation of protein-protein interaction surfaces on the androgen receptor (AR), a surrogate assay of receptor conformation, could be used in a prospective manner to define the pharmacological activity of bound ligands. To this end, we identified over 150 proteins/polypeptides whose ability to interact with AR is influenced in a differential manner by ligand binding. The most discriminatory of these protein-AR interactions were used to develop a robust compound-profiling tool that enabled the separation of ligands into functionally distinguishable classes. Importantly, the ligands within each class exhibited similar pharmacological activities, a result that highlights the relationship between receptor structure and activity and provides direction for the discovery of novel AR modulators.
Norris
John David
JD
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Joseph
James David
JD
Sherk
Andrea Barreto
AB
Juzumiene
Dalia
D
Turnbull
Philip Stewart
PS
Rafferty
Stephen William
SW
Cui
Huaxia
H
Anderson
Erin
E
Fan
Daju
D
Dye
Delita Arnelle
DA
Deng
Xiang
X
Kazmin
Dmitri
D
Chang
Ching-Yi
CY
Willson
Timothy Mark
TM
McDonnell
Donald Patrick
DP
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008024:Ligands; D011485:Protein Binding; D011487:Protein Conformation / Q000187:drug effects; D025941:Protein Interaction Mapping; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects
D008024:Ligands; D011944:Receptors, Androgen