View source for 9gqa


==The FK1 domain of FKBP51 in complex with the macrocyclic SAFit analog p5(2,2)-Diol-IV==
<StructureSection load='9gqa' size='340' side='right'caption='[[9gqa]], [[Resolution|resolution]] 1.93&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9gqa]] is a 2 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=9GQA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9GQA 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]] 1.93&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1IN7:(2~{S},9~{S},14~{S},15~{R})-2-cyclohexyl-20,23-dimethoxy-14,15-bis(oxidanyl)-11,18-dioxa-4-azatricyclo[17.2.2.0^{4,9}]tricosa-1(21),19,22-triene-3,10-dione'>A1IN7</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=9gqa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9gqa OCA], [https://pdbe.org/9gqa PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9gqa RCSB], [https://www.ebi.ac.uk/pdbsum/9gqa PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9gqa 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 ==
Macrocycles are increasingly considered as promising modalities to target challenging intracellular proteins. However, strategies for transitioning from active linear starting points to improved macrocycles are still underdeveloped. Here we explored the derivatization of linkers as an approach for macrocycle optimization. Using the FK506-binding protein 51 (FKBP51) as a model system we prepared &gt;140 macrocycles with systematically derivatized linkers. Two backbones were identified as promising frameworks for subsequent optimization. Surprisingly, co-crystal structure analyses revealed that these chemical templates represent an ensemble of three-dimensional (3D) conformations that can give rise to several distinct 3D-scaffolds. This resulted in a set of macrocycles with consistently improved affinity, plasma stability, and aqueous solubility compared to the linear precursors or the non-functionalized macrocycles. Our results highlight linkers as an opportunity for macrocyclic drug development, show how linker derivatization can improve the performance of macrocycles, and emphasizes the need to track macrocyclic scaffold evolution at a three-dimensional level.

Conformationally Restricted Macrocycles as Improved FKBP51 Inhibitors Enabled by Systematic Linker Derivatization.,Spiske M, Meyners C, Bauder M, Repity M, Brudy C, Sugiarto WO, Achaq H, Geiger TM, Hausch F Angew Chem Int Ed Engl. 2025 Jan 3:e202418511. doi: 10.1002/anie.202418511. PMID:39752587<ref>PMID:39752587</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9gqa" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Hausch F]]
[[Category: Meyners C]]
[[Category: Spiske M]]