1gs4
From Proteopedia
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==Overview== | ==Overview== | ||
| - | The crystal structure of a mutant androgen receptor (AR) ligand-binding | + | 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== | ==Disease== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Carrondo, M | + | [[Category: Carrondo, M A.]] |
[[Category: Coelho, R.]] | [[Category: Coelho, R.]] | ||
[[Category: Crusius, K.]] | [[Category: Crusius, K.]] | ||
[[Category: Donner, P.]] | [[Category: Donner, P.]] | ||
[[Category: Egner, U.]] | [[Category: Egner, U.]] | ||
| - | [[Category: Matias, P | + | [[Category: Matias, P M.]] |
[[Category: Thomaz, M.]] | [[Category: Thomaz, M.]] | ||
[[Category: Wegg, A.]] | [[Category: Wegg, A.]] | ||
| - | [[Category: Zhao, X | + | [[Category: Zhao, X Y.]] |
[[Category: PO4]] | [[Category: PO4]] | ||
[[Category: ZK5]] | [[Category: ZK5]] | ||
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[[Category: prostate cancer]] | [[Category: prostate cancer]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:53:21 2008'' |
Revision as of 10:53, 21 February 2008
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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 and as ligands. Known structural/functional Site: . 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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