1gs4

From Proteopedia

Revision as of 14:12, 5 November 2007

STRUCTURAL BASIS FOR THE GLUCOCORTICOID RESPONSE IN A MUTANT HUMAN ANDROGEN RECEPTOR (ARCCR) DERIVED FROM AN ANDROGEN-INDEPENDENT PROSTATE CANCER

Overview

The crystal structure of a mutant androgen receptor (AR) ligand-binding, domain (LBD) in complex with the agonist 9alpha-fluorocortisol has been, determined at 1.95 A resolution. This mutant AR contains two mutations, (L701H and T877A) and was previously reported as a high-affinity, cortisol/cortisone responsive AR (AR(ccr)) isolated from the, androgen-independent human prostate cancer cell lines MDA PCa 2a and 2b, (Zhao et al. Nature Med. 2000, 6, 703-6). The three-dimensional structure, of the AR(ccr) LBD complexed with 9alpha-fluorocortisol shows the typical, conformation of an agonist-bound nuclear receptor in which helix 12 is, precisely positioned as a "lid" for the ligand-binding pocket. Binding of, 9alpha-fluorocortisol to the AR(ccr) involves favorable hydrogen bond, patterns on the C17 and C21 substituents of the ligand due to the, mutations at 701 and 877 in the AR(ccr). Our studies provide the first, structural explanation for the glucocorticoid activation of AR(ccr), which, is important for the development of new therapeutic treatments for, androgen-independent prostate cancer.

About this Structure

1GS4 is a Single protein structure of sequence from Homo sapiens with PO4 and ZK5 as ligands. Structure known Active Site: AC1. Full crystallographic information is available from OCA.

Reference

Structural basis for the glucocorticoid response in a mutant human androgen receptor (AR(ccr)) derived from an androgen-independent prostate cancer., Matias PM, Carrondo MA, Coelho R, Thomaz M, Zhao XY, Wegg A, Crusius K, Egner U, Donner P, J Med Chem. 2002 Mar 28;45(7):1439-46. PMID:11906285

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