2pnu

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(New page: 200px<br /> <applet load="2pnu" size="450" color="white" frame="true" align="right" spinBox="true" caption="2pnu, resolution 1.650&Aring;" /> '''Crystal structure ...)
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[[Image:2pnu.gif|left|200px]]<br />
 
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<applet load="2pnu" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="2pnu, resolution 1.650&Aring;" />
 
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'''Crystal structure of human androgen receptor ligand-binding domain in complex with EM-5744'''<br />
 
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==Overview==
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==Crystal structure of human androgen receptor ligand-binding domain in complex with EM-5744==
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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.
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<StructureSection load='2pnu' size='340' side='right'caption='[[2pnu]], [[Resolution|resolution]] 1.65&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2pnu]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2PNU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2PNU FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.65&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DTT:2,3-DIHYDROXY-1,4-DITHIOBUTANE'>DTT</scene>, <scene name='pdbligand=ENM:(5S,8R,9S,10S,13R,14S,17S)-13-{2-[(3,5-DIFLUOROBENZYL)OXY]ETHYL}-17-HYDROXY-10-METHYLHEXADECAHYDRO-3H-CYCLOPENTA[A]PHENANTHREN-3-ONE'>ENM</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2pnu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2pnu OCA], [https://pdbe.org/2pnu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2pnu RCSB], [https://www.ebi.ac.uk/pdbsum/2pnu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2pnu ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/ANDR_HUMAN ANDR_HUMAN] Defects in AR are the cause of androgen insensitivity syndrome (AIS) [MIM:[https://omim.org/entry/300068 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.<ref>PMID:2594783</ref> <ref>PMID:8413310</ref> <ref>PMID:1775137</ref> <ref>PMID:16129672</ref> <ref>PMID:2082179</ref> <ref>PMID:1999491</ref> <ref>PMID:1609793</ref> <ref>PMID:1426313</ref> <ref>PMID:1487249</ref> <ref>PMID:1307250</ref> <ref>PMID:1569163</ref> <ref>PMID:1464650</ref> <ref>PMID:1430233</ref> <ref>PMID:1316540</ref> <ref>PMID:1480178</ref> <ref>PMID:8224266</ref> <ref>PMID:8103398</ref> <ref>PMID:8281140</ref> <ref>PMID:8325950</ref> <ref>PMID:8096390</ref> <ref>PMID:8446106</ref> [:]<ref>PMID:8162033</ref> <ref>PMID:7981687</ref> <ref>PMID:7981689</ref> <ref>PMID:7962294</ref> <ref>PMID:8040309</ref> <ref>PMID:7929841</ref> <ref>PMID:7993455</ref> <ref>PMID:7970939</ref> <ref>PMID:8830623</ref> <ref>PMID:7641413</ref> <ref>PMID:7671849</ref> <ref>PMID:7633398</ref> <ref>PMID:7537149</ref> <ref>PMID:7581399</ref> <ref>PMID:8723113</ref> <ref>PMID:9039340</ref> <ref>PMID:9001799</ref> <ref>PMID:8626869</ref> <ref>PMID:8768864</ref> <ref>PMID:8918984</ref> <ref>PMID:8683794</ref> <ref>PMID:8647313</ref> <ref>PMID:8809734</ref> <ref>PMID:9106550</ref> <ref>PMID:9160185</ref> <ref>PMID:9007482</ref> <ref>PMID:8990010</ref> <ref>PMID:9255042</ref> <ref>PMID:9252933</ref> <ref>PMID:9328206</ref> <ref>PMID:9302173</ref> <ref>PMID:9544375</ref> <ref>PMID:9698822</ref> <ref>PMID:9788719</ref> <ref>PMID:9610419</ref> <ref>PMID:9856504</ref> <ref>PMID:9554754</ref> [:]<ref>PMID:9851768</ref> <ref>PMID:9627582</ref> <ref>PMID:10571951</ref> <ref>PMID:10221692</ref> <ref>PMID:10404311</ref> <ref>PMID:10022458</ref> <ref>PMID:10221770</ref> <ref>PMID:10590024</ref> <ref>PMID:10458483</ref> <ref>PMID:10690872</ref> <ref>PMID:11587068</ref> <ref>PMID:11744994</ref> <ref>PMID:16595706</ref> Defects in AR are the cause of spinal and bulbar muscular atrophy X-linked type 1 (SMAX1) [MIM:[https://omim.org/entry/313200 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.<ref>PMID:15851746</ref> 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:[https://omim.org/entry/312300 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.
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== Function ==
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[https://www.uniprot.org/uniprot/ANDR_HUMAN 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.<ref>PMID:14664718</ref> <ref>PMID:18084323</ref> <ref>PMID:19345326</ref> <ref>PMID:20980437</ref> <ref>PMID:15563469</ref> <ref>PMID:17591767</ref> <ref>PMID:17911242</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/pn/2pnu_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2pnu ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Antiandrogens are 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 carboxyl-terminal helix 12, which blocks the ligand-dependent 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 5alpha-dihydrotestosterone-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 Gln(738), Met(742), and His(874) that explain both the high affinity of this compound and the inability of its bulky chain to prevent the repositioning of H12. This structural information will be helpful to refine the structure of the chains placed on the C18 atom to obtain efficient H12-directed steroidal antiandrogens.
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==Disease==
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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, de Jesus-Tran KP, Legrand P, Ciobanu LC, Frechette Y, Labrecque R, Singh SM, Labrie F, Breton R J Biol Chem. 2007 Oct 19;282(42):30910-9. Epub 2007 Aug 21. PMID:17711855<ref>PMID:17711855</ref>
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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]]
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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2PNU is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with SO4, ENM, DTT and MES as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2PNU OCA].
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</div>
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<div class="pdbe-citations 2pnu" style="background-color:#fffaf0;"></div>
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==Reference==
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==See Also==
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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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17711855 17711855]
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*[[Androgen receptor 3D structures|Androgen receptor 3D structures]]
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*[[FKBP 3D structures|FKBP 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Single protein]]
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[[Category: Large Structures]]
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[[Category: Breton, R.]]
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[[Category: Breton R]]
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[[Category: Cantin, L.]]
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[[Category: Cantin L]]
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[[Category: Ciobanu, C.L.]]
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[[Category: Ciobanu CL]]
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[[Category: Couture, J.F.]]
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[[Category: Couture JF]]
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[[Category: Faucher, F.]]
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[[Category: Faucher F]]
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[[Category: Jesus-Tran, K.Pereira.de.]]
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[[Category: Labrie F]]
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[[Category: Labrie, F.]]
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[[Category: Legrand P]]
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[[Category: Legrand, P.]]
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[[Category: Pereira de Jesus-Tran K]]
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[[Category: Singh, S.M.]]
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[[Category: Singh SM]]
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[[Category: DTT]]
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[[Category: ENM]]
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[[Category: MES]]
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[[Category: SO4]]
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[[Category: androgen]]
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[[Category: androgen receptor]]
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[[Category: dht]]
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[[Category: har]]
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[[Category: hormone/gene regulation complex]]
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[[Category: lbd]]
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[[Category: ligand binding domain]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 23:25:42 2007''
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Current revision

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

PDB ID 2pnu

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