View source for 9qda


==The FK1 domain of FKBP51 in complex with the macrocyclic SAFit analog 29b==
<StructureSection load='9qda' size='340' side='right'caption='[[9qda]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9qda]] 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=9QDA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9QDA 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&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1I55:(2~{S},9~{S},12~{R})-2-cyclohexyl-19,22-dimethoxy-12-methyl-11,14,17-trioxa-4-azatricyclo[16.2.2.0^{4,9}]docosa-1(21),18(22),19-triene-3,10-dione'>A1I55</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=9qda FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9qda OCA], [https://pdbe.org/9qda PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9qda RCSB], [https://www.ebi.ac.uk/pdbsum/9qda PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9qda 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 promising drug modalities that can enable unique ways of conformational preorganization, but how even minor modifications to a macrocyclic scaffold influence the conformational preorganization remains poorly understood. Here, we show how macrocyclization and further derivatization of the linker region can improve affinity, selectivity, and plasma stability in a highly atom-efficient manner. A single, solvent-exposed methyl group was found to improve binding affinity up to 10x over the nonmethylated analog. This led to highly ligand-efficient macrocycles with good brain permeability, improved solubility, and a promising in vivo profile for the FK506-binding protein 51 (FKBP51), a key regulator of the human stress response. Using high-resolution cocrystal structures and molecular dynamics simulations, we found that small linker variations can be tuned to shift the orientation of a key carbonyl group into an advantageous position. This effect is specific to macrocycles, highlighting their potential for fine-tuned adjustments to enable desired properties.

Linker Modification Enables Control of Key Functional Group Orientation in Macrocycles.,Brudy C, Ruijsenaars E, Meyners C, Sugiarto WO, Achaq H, Spiske M, Buffa V, Springer M, Repity M, Weller A, Haferkamp U, Pless O, Muschong P, Miltner D, Mezler M, Schmidt MV, Riniker S, Hausch F J Med Chem. 2025 Nov 22. doi: 10.1021/acs.jmedchem.5c00958. PMID:41273793<ref>PMID:41273793</ref>

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