9GQE
The FK1 domain of FKBP51 in complex with the macrocyclic SAFit analog m5(2,4)-H2
This is a non-PDB format compatible entry.
Summary for 9GQE
| Entry DOI | 10.2210/pdb9gqe/pdb |
| Descriptor | Peptidyl-prolyl cis-trans isomerase FKBP5, (2~{S},9~{S})-2-cyclohexyl-23,24-dimethoxy-11,17,21-trioxa-4-azatricyclo[20.3.1.0^{4,9}]hexacosa-1(26),22,24-triene-3,10-dione (3 entities in total) |
| Functional Keywords | fkbp, inhibitor, safit, macrocycle, complex, isomerase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 29071.41 |
| Authors | |
| Primary citation | Spiske, M.,Meyners, C.,Bauder, M.,Repity, M.,Brudy, C.,Sugiarto, W.O.,Achaq, H.,Geiger, T.M.,Hausch, F. Conformationally Restricted Macrocycles as Improved FKBP51 Inhibitors Enabled by Systematic Linker Derivatization. Angew.Chem.Int.Ed.Engl., :e202418511-e202418511, 2025 Cited by PubMed Abstract: 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 >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. PubMed: 39752587DOI: 10.1002/anie.202418511 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.5 Å) |
Structure validation
Download full validation report
