2pnu

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spinqualitylabelsall models 2pnu, resolution 1.650Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Crystal structure of human androgen receptor ligand-binding domain in complex with EM-5744

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

The androgen receptor (AR) mediates the action of androgens in normal, conditions as well as in pathological states. Antiandrogens are thus, commonly used to treat androgen-dependent disorders. The currently used, drugs unfortunately possess very weak affinity for the human AR (hAR), thus indicating the need to develop new high-affinity steroidal, antiandrogens. Our compounds are specially designed to impede, repositioning of the mobile carboxy-terminal helix 12, which blocks the, ligand-dependant transactivation function (AF-2) located in the AR, ligand-binding domain (ARLBD). Using crystal structures of the hARLBD, we, first found that H12 could be directly reached from the ligand-binding, pocket (LBP) by a chain positioned on the C18 atom of an androgen steroid, nucleus. A set of DHT-derived molecules bearing various C18 chains were, thus synthesized and tested for their capacity to bind hAR and act as, antagonists. Although most of those having very high affinity for hAR were, agonists, several very potent antagonists were obtained, confirming the, structural importance of the C18 chain. To understand the role of the C18, chain in their agonistic/antagonistic properties, the structure of the, hARLBD complexed with one of these agonists, EM5744, was determined at a, 1.65 A resolution. We have identified new interactions involving Gln738, Met742 and His874 that explain both the high-affinity of this compound and, the inability of its bulky chain to prevent the repositioning of H12., These structural informations will be helpful to refine the structure of, the chains placed on the C18 atom in order to obtain efficient, H12-directed steroidal antiandrogens.

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

2PNU is a Single protein structure of sequence from Homo sapiens with SO4, ENM, DTT and MES as ligands. Full crystallographic information is available from OCA.

Reference

Structural characterization of the human androgen receptor ligand-binding domain complexed with EM5744, a rationally-designed steroidal ligand bearing a bulky chain directed toward helix 12., Cantin L, Faucher F, Couture JF, Pereira de Jesus-Tran K, Legrand P, Ciobanu LC, Frechette Y, Labrecque R, Singh SM, Labrie F, Breton R, J Biol Chem. 2007 Aug 21;. PMID:17711855

Page seeded by OCA on Mon Nov 12 23:25:42 2007