1Z95

Crystal Structure of the Androgen Receptor Ligand-binding Domain W741L Mutant Complex with R-bicalutamide

Summary for 1Z95

• Entry DOI: 10.2210/pdb1z95/pdb
• Descriptor: Androgen Receptor, SULFATE ION, R-BICALUTAMIDE, ... (4 entities in total)
• Functional Keywords: steroid hormones; receptors; cellular proliferation; cellular differentiation, transcription regulation, receptor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: P10275
• Total number of polymer chains: 1
• Total formula weight: 29173.11

Authors

Bohl, C.E.,Gao, W.,Miller, D.D.,Bell, C.E.,Dalton, J.T. (deposition date: 2005-03-31, release date: 2005-04-19, Last modification date: 2023-08-23)

Primary citation

Bohl, C.E.,Gao, W.,Miller, D.D.,Bell, C.E.,Dalton, J.T.
Structural basis for antagonism and resistance of bicalutamide in prostate cancer.
Proc.Natl.Acad.Sci.Usa, 102:6201-6206, 2005

PubMed Abstract: Carcinoma of the prostate is the most commonly diagnosed cancer in men. The current pharmacological treatment of choice for progressive androgen-dependent prostate cancer is the nonsteroidal antiandrogen, bicalutamide, either as monotherapy or with adjuvant castration or luteinizing hormone-releasing hormone superagonists to block the synthesis of endogenous testosterone. To date, no nonsteroidal or antagonist-bound androgen receptor (AR) structure is available. We solved the x-ray crystal structure of the mutant W741L AR ligand-binding domain bound to R-bicalutamide at 1.8-A resolution. This mutation confers agonist activity to bicalutamide and is likely involved in bicalutamide withdrawal syndrome. The three-dimensional structure demonstrates that the B ring of R-bicalutamide in the W741L mutant is accommodated at the location of the indole ring of Trp-741 in the WT AR bound to dihydrotestosterone. Knowledge of the binding mechanism for R-bicalutamide will provide molecular rationale for the development of new antiandrogens and selective AR modulators.

PubMed: 15833816
DOI: 10.1073/pnas.0500381102

Experimental method

X-RAY DIFFRACTION (1.8 Å)