title: Differential presentation of protein interaction surfaces on the androgen receptor defines the pharmacological actions of bound ligands.
abstract: 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.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: John David
authors.initials: JD
authors.lastname: Norris
authors.forename: James David
authors.initials: JD
authors.lastname: Joseph
authors.forename: Andrea Barreto
authors.initials: AB
authors.lastname: Sherk
authors.forename: Dalia
authors.initials: D
authors.lastname: Juzumiene
authors.forename: Philip Stewart
authors.initials: PS
authors.lastname: Turnbull
authors.forename: Stephen William
authors.initials: SW
authors.lastname: Rafferty
authors.forename: Huaxia
authors.initials: H
authors.lastname: Cui
authors.forename: Erin
authors.initials: E
authors.lastname: Anderson
authors.forename: Daju
authors.initials: D
authors.lastname: Fan
authors.forename: Delita Arnelle
authors.initials: DA
authors.lastname: Dye
authors.forename: Xiang
authors.initials: X
authors.lastname: Deng
authors.forename: Dmitri
authors.initials: D
authors.lastname: Kazmin
authors.forename: Ching-Yi
authors.initials: CY
authors.lastname: Chang
authors.forename: Timothy Mark
authors.initials: TM
authors.lastname: Willson
authors.forename: Donald Patrick
authors.initials: DP
authors.lastname: McDonnell
mesh_terms: 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
chemical_list: D008024:Ligands; D011944:Receptors, Androgen