7APQ
The Fk1 domain of FKBP51 in complex with (1S,5S,6R)-10-(benzo[d]thiazol-6-ylsulfonyl)-5-(methoxymethyl)-3-(pyridin-2-ylmethyl)-3,10-diazabicyclo[4.3.1]decan-2-one
Summary for 7APQ
| Entry DOI | 10.2210/pdb7apq/pdb |
| Descriptor | Peptidyl-prolyl cis-trans isomerase FKBP5, (1~{S},5~{S},6~{R})-10-(1,3-benzothiazol-6-ylsulfonyl)-5-(methoxymethyl)-3-(pyridin-2-ylmethyl)-3,10-diazabicyclo[4.3.1]decan-2-one (3 entities in total) |
| Functional Keywords | conformation analysis, density functional calculations, fkbps, magic methyl, isomerase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 14512.68 |
| Authors | Kolos, M.J.,Pomplun, S.,Riess, B.,Purder, P.,Voll, M.A.,Merz, S.,Bracher, A.,Meyners, C.,Krewald, V.,Hausch, F. (deposition date: 2020-10-19, release date: 2021-11-10, Last modification date: 2024-01-31) |
| Primary citation | Kolos, J.M.,Pomplun, S.,Jung, S.,Riess, B.,Purder, P.L.,Voll, A.M.,Merz, S.,Gnatzy, M.,Geiger, T.M.,Quist-Lokken, I.,Jatzlau, J.,Knaus, P.,Holien, T.,Bracher, A.,Meyners, C.,Czodrowski, P.,Krewald, V.,Hausch, F. Picomolar FKBP inhibitors enabled by a single water-displacing methyl group in bicyclic [4.3.1] aza-amides. Chem Sci, 12:14758-14765, 2021 Cited by PubMed Abstract: Methyl groups can have profound effects in drug discovery but the underlying mechanisms are diverse and incompletely understood. Here we report the stereospecific effect of a single, solvent-exposed methyl group in bicyclic [4.3.1] aza-amides, robustly leading to a 2 to 10-fold increase in binding affinity for FK506-binding proteins (FKBPs). This resulted in the most potent and efficient FKBP ligands known to date. By a combination of co-crystal structures, isothermal titration calorimetry (ITC), density-functional theory (DFT), and 3D reference interaction site model (3D-RISM) calculations we elucidated the origin of the observed affinity boost, which was purely entropically driven and relied on the displacement of a water molecule at the protein-ligand-bulk solvent interface. The best compounds potently occupied FKBPs in cells and enhanced bone morphogenic protein (BMP) signaling. Our results show how subtle manipulation of the solvent network can be used to design atom-efficient ligands for difficult, solvent-exposed binding pockets. PubMed: 34820091DOI: 10.1039/d1sc04638a PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.09 Å) |
Structure validation
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