View source for 7awf


==The Fk1 domain of FKBP51 in complex with (2R,5S,12R)-12-cyclohexyl-2-[2-(3,4-dimethoxyphenyl)ethyl]-15,15,16-trimethyl-3,19-dioxa-10,13,16-triazatricyclo[18.3.1.0^5,^10]tetracosa-1(24),20,22-triene-4,11,14,17-tetrone==
<StructureSection load='7awf' size='340' side='right'caption='[[7awf]], [[Resolution|resolution]] 1.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7awf]] 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=7AWF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AWF 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]] 1.4&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=S8N:(2~{R},5~{S},12~{R})-12-cyclohexyl-2-[2-(3,4-dimethoxyphenyl)ethyl]-15,15,16-trimethyl-3,19-dioxa-10,13,16-triazatricyclo[18.3.1.0^{5,10}]tetracosa-1(24),20,22-triene-4,11,14,17-tetrone'>S8N</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=7awf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7awf OCA], [https://pdbe.org/7awf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7awf RCSB], [https://www.ebi.ac.uk/pdbsum/7awf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7awf 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 ==
Subtype selectivity represents a recurring challenge in many drug discovery campaigns. A typical example is the FK506 binding protein 51 (FKBP51), which has emerged as an attractive drug target for mood disorders, obesity and chronic pain. The most advanced FKBP51 ligands of the SAFit class are highly selective vs. FKBP52 but poorly discriminate against the homologs and off-targets FKBP12 and FKBP12.6. During a macrocyclization pilot study, we surprisingly observed that many of these macrocyclic analogs have unanticipated and unprecedented preference for FKBP51 over FKBP12 and FKBP12.6. Structural studies revealed that these macrocycles bind with a new binding mode featuring a transient conformation, which is disfavored for the small FKBPs. Using a conformation-sensitive assay we show that this binding mode occurs in solution and is characteristic for this new class of compounds. The discovered macrocycles are non-immunosuppressive, engage FKBP51 in cells, and block the cellular effect of FKBP51 on IKKalpha. Our findings provide a new chemical scaffold for improved FKBP51 ligands and the structural basis for enhanced selectivity.

Macrocyclic FKBP51 ligands define a transient binding mode with enhanced selectivity.,Voll AM, Meyners C, Taubert MC, Bajaj T, Heymann T, Merz S, Charalampidou A, Kolos J, Purder PL, Geiger TM, Wessig P, Gassen NC, Bracher A, Hausch F Angew Chem Int Ed Engl. 2021 Apr 11. doi: 10.1002/anie.202017352. PMID:33843131<ref>PMID:33843131</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7awf" 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: Hausch F]]
[[Category: Heymann T]]
[[Category: Merz S]]
[[Category: Meyners C]]
[[Category: Purder P]]
[[Category: Voll MA]]