1gs4
From Proteopedia
| Line 6: | Line 6: | ||
==Overview== | ==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. | 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. | ||
| + | |||
| + | ==Disease== | ||
| + | Known diseases associated with this structure: Androgen insensitivity OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=313700 313700]], Breast cancer, male, with Reifenstein syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=313700 313700]], Hypospadias, perineal OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=313700 313700]], Prostate cancer OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=313700 313700]], Prostate cancer, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=313700 313700]], Spinal and bulbar muscular atrophy of Kennedy OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=313700 313700]] | ||
==About this Structure== | ==About this Structure== | ||
| Line 30: | Line 33: | ||
[[Category: prostate cancer]] | [[Category: prostate cancer]] | ||
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov | + | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 17:08:33 2007'' |
Revision as of 15:02, 12 November 2007
|
STRUCTURAL BASIS FOR THE GLUCOCORTICOID RESPONSE IN A MUTANT HUMAN ANDROGEN RECEPTOR (ARCCR) DERIVED FROM AN ANDROGEN-INDEPENDENT PROSTATE CANCER
Contents |
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.
Disease
Known diseases associated with this structure: Androgen insensitivity OMIM:[313700], Breast cancer, male, with Reifenstein syndrome OMIM:[313700], Hypospadias, perineal OMIM:[313700], Prostate cancer OMIM:[313700], Prostate cancer, susceptibility to OMIM:[313700], Spinal and bulbar muscular atrophy of Kennedy OMIM:[313700]
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
Page seeded by OCA on Mon Nov 12 17:08:33 2007
