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8e1a: Difference between revisions

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== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[8e1a]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=4u4k 4u4k]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8E1A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8E1A FirstGlance]. <br>
<table><tr><td colspan='2'>[[8e1a]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=4u4k 4u4k]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8E1A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8E1A FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3E0:4-[4-(3-FLUORO-2-METHOXYPHENYL)-1,3-THIAZOL-2-YL]MORPHOLINE'>3E0</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.2&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3E0:4-[4-(3-FLUORO-2-METHOXYPHENYL)-1,3-THIAZOL-2-YL]MORPHOLINE'>3E0</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8e1a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8e1a OCA], [https://pdbe.org/8e1a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8e1a RCSB], [https://www.ebi.ac.uk/pdbsum/8e1a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8e1a ProSAT]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8e1a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8e1a OCA], [https://pdbe.org/8e1a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8e1a RCSB], [https://www.ebi.ac.uk/pdbsum/8e1a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8e1a ProSAT]</span></td></tr>
</table>
</table>
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== Function ==
== Function ==
[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>  
[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>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The mutation-driven transformation of clinical anti-androgen drugs into agonists of the human androgen receptor (AR) represents a major challenge for the treatment of prostate cancer patients. To address this challenge, we have developed a novel class of inhibitors targeting the DNA-binding domain (DBD) of the receptor, which is distanced from the androgen binding site (ABS) targeted by all conventional anti-AR drugs and prone to resistant mutations. While many members of the developed 4-(4-phenylthiazol-2-yl)morpholine series of AR-DBD inhibitors demonstrated the effective suppression of wild-type AR, a few represented by 4-(4-(3-fluoro-2-methoxyphenyl)thiazol-2-yl)morpholine (VPC14368) exhibited a partial agonistic effect toward the mutated T878A form of the receptor, implying their cross-interaction with the AR ABS. To study the molecular basis of the observed cross-reactivity, we co-crystallized the T878A mutated form of the AR ligand binding domain (LBD) with a bound VPC14368 molecule. Computational modelling revealed that helix 12 of AR undergoes a characteristic shift upon VPC14368 binding causing the agonistic behaviour. Based on the obtained structural data we then designed derivatives of VPC14368 to successfully eliminate the cross-reactivity towards the AR ABS, while maintaining significant anti-AR DBD potency.
Structure-Based Study to Overcome Cross-Reactivity of Novel Androgen Receptor Inhibitors.,Radaeva M, Li H, LeBlanc E, Dalal K, Ban F, Ciesielski F, Chow B, Morin H, Awrey S, Singh K, Rennie PS, Lallous N, Cherkasov A Cells. 2022 Sep 7;11(18). pii: cells11182785. doi: 10.3390/cells11182785. PMID:36139361<ref>PMID:36139361</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8e1a" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>

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