View source for 6saf


==The Fk1 domain of FKBP51 in complex with (S)-(R)-3-(3,4-dimethoxyphenyl)-1-(3-(2-morpholinoethoxy)phenyl)propyl 1-((1R,4aR,8aR)-4-oxodecahydronaphthalene-1-carbonyl)piperidine-2-carboxylate==
<StructureSection load='6saf' size='340' side='right'caption='[[6saf]], [[Resolution|resolution]] 2.05&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6saf]] 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=6SAF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6SAF FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.05&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=L2Q:[(1~{R})-3-(3,4-dimethoxyphenyl)-1-[3-(2-morpholin-4-ylethoxy)phenyl]propyl]+(2~{S})-1-[[(1~{R},4~{a}~{R},8~{a}~{R})-4-oxidanylidene-2,3,4~{a},5,6,7,8,8~{a}-octahydro-1~{H}-naphthalen-1-yl]carbonyl]piperidine-2-carboxylate'>L2Q</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=6saf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6saf OCA], [https://pdbe.org/6saf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6saf RCSB], [https://www.ebi.ac.uk/pdbsum/6saf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6saf ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/FKBP5_HUMAN FKBP5_HUMAN] Interacts with functionally mature heterooligomeric progesterone receptor complexes along with HSP90 and TEBP.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Selective inhibition of FKBP51 has emerged as possible novel treatment for diseases like major depressive disorder, obesity, chronic pain and certain cancers. The current FKBP51 inhibitors are rather large, flexible and have to be further optimized. Using a structure-based rigidification strategy, we hereby report the design and synthesis of a novel promising bicyclic scaffold for FKBP51 ligands. The structure-activity analysis revealed the decalin scaffold as the best moiety for the selectivity-enabling subpocket of FBKP51. The resulting compounds retain high potency for FKBP51 and excellent selectivity over the close homolog FKBP52. With the cocrystal structure of an advanced ligand in this novel series, we show how the decalin locks the key selectivity-inducing cyclohexyl moiety of the ligand in a conformation typical for FKBP51-selective binding. The best compound 29 produces cell death in a HeLa-derived KB cell line, a cellular model of cervical adenocarcinoma, where FKBP51 is highly overexpressed. Our results show how FKBP51 inhibitors can be rigidified and extended while preserving FKBP51 selectivity. Such inhibitors might be novel tools in the treatment of human cancers with deregulated FKBP51.

A novel decalin-based bicyclic scaffold for FKBP51-selective ligands.,Feng X, Sippel C, Knaup F, Bracher A, Staibano S, Romano MF, Hausch F J Med Chem. 2019 Dec 4. doi: 10.1021/acs.jmedchem.9b01157. PMID:31800244<ref>PMID:31800244</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6saf" style="background-color:#fffaf0;"></div>

==See Also==
*[[FKBP 3D structures|FKBP 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Bracher A]]
[[Category: Feng X]]
[[Category: Hausch F]]
[[Category: Knaup F]]
[[Category: Romano MF]]
[[Category: Sippel C]]
[[Category: Staibano S]]