2pix | pdb_00002pix

AR LBD with small molecule

spinqualitylabelsall models 2pix, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2pix is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: DHT, FLF Related: 2pin, 2pio, 2pip, 2piq, 2pir, 2pit, 2piu, 2piv, 2piw, 2pkl Gene: AR, DHTR, NR3C4 (HUMAN) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [ANDR_HUMAN] Defects in AR are the cause of androgen insensitivity syndrome (AIS) [MIM:300068]; previously known as testicular feminization syndrome (TFM). AIS is an X-linked recessive form of pseudohermaphroditism due end-organ resistance to androgen. Affected males have female external genitalia, female breast development, blind vagina, absent uterus and female adnexa, and abdominal or inguinal testes, despite a normal 46,XY karyotype. [:] [:] Defects in AR are the cause of spinal and bulbar muscular atrophy X-linked type 1 (SMAX1) [MIM:313200]; also known as Kennedy disease. SMAX1 is an X-linked recessive form of spinal muscular atrophy. Spinal muscular atrophy refers to a group of neuromuscular disorders characterized by degeneration of the anterior horn cells of the spinal cord, leading to symmetrical muscle weakness and atrophy. SMAX1 occurs only in men. Age at onset is usually in the third to fifth decade of life, but earlier involvement has been reported. It is characterized by slowly progressive limb and bulbar muscle weakness with fasciculations, muscle atrophy, and gynecomastia. The disorder is clinically similar to classic forms of autosomal spinal muscular atrophy. Note=Caused by trinucleotide CAG repeat expansion. In SMAX1 patients the number of Gln ranges from 38 to 62. Longer expansions result in earlier onset and more severe clinical manifestations of the disease. Note=Defects in AR may play a role in metastatic prostate cancer. The mutated receptor stimulates prostate growth and metastases development despite of androgen ablation. This treatment can reduce primary and metastatic lesions probably by inducing apoptosis of tumor cells when they express the wild-type receptor. Defects in AR are the cause of androgen insensitivity syndrome partial (PAIS) [MIM:312300]; also known as Reifenstein syndrome. PAIS is characterized by hypospadias, hypogonadism, gynecomastia, genital ambiguity, normal XY karyotype, and a pedigree pattern consistent with X-linked recessive inheritance. Some patients present azoospermia or severe oligospermia without other clinical manifestations. Function [ANDR_HUMAN] Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Transcription factor activity is modulated by bound coactivator and corepressor proteins. Transcription activation is down-regulated by NR0B2. Activated, but not phosphorylated, by HIPK3 and ZIPK/DAPK3. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed Current approaches to inhibit nuclear receptor (NR) activity target the hormone binding pocket but face limitations. We have proposed that inhibitors, which bind to nuclear receptor surfaces that mediate assembly of the receptor's binding partners, might overcome some of these limitations. The androgen receptor (AR) plays a central role in prostate cancer, but conventional inhibitors lose effectiveness as cancer treatments because anti-androgen resistance usually develops. We conducted functional and x-ray screens to identify compounds that bind the AR surface and block binding of coactivators for AR activation function 2 (AF-2). Four compounds that block coactivator binding in solution with IC(50) approximately 50 microM and inhibit AF-2 activity in cells were detected: three nonsteroidal antiinflammatory drugs and the thyroid hormone 3,3',5-triiodothyroacetic acid. Although visualization of compounds at the AR surface reveals weak binding at AF-2, the most potent inhibitors bind preferentially to a previously unknown regulatory surface cleft termed binding function (BF)-3, which is a known target for mutations in prostate cancer and androgen insensitivity syndrome. X-ray structural analysis reveals that 3,3',5-triiodothyroacetic acid binding to BF-3 remodels the adjacent interaction site AF-2 to weaken coactivator binding. Mutation of residues that form BF-3 inhibits AR function and AR AF-2 activity. We propose that BF-3 is a previously unrecognized allosteric regulatory site needed for AR activity in vivo and a possible pharmaceutical target. A surface on the androgen receptor that allosterically regulates coactivator binding.,Estebanez-Perpina E, Arnold LA, Nguyen P, Rodrigues ED, Mar E, Bateman R, Pallai P, Shokat KM, Baxter JD, Guy RK, Webb P, Fletterick RJ Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):16074-9. Epub 2007 Oct 2. PMID:17911242 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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