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

spinqualitylabelsall models 7apq, resolution 1.09Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7apq is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.09Å Ligands: RQW Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function FKBP5_HUMAN Interacts with functionally mature heterooligomeric progesterone receptor complexes along with HSP90 and TEBP. Publication Abstract from PubMed 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. Picomolar FKBP inhibitors enabled by a single water-displacing methyl group in bicyclic [4.3.1] aza-amides.,Kolos JM, Pomplun S, Jung S, Riess B, Purder PL, Voll AM, Merz S, Gnatzy M, Geiger TM, Quist-Lokken I, Jatzlau J, Knaus P, Holien T, Bracher A, Meyners C, Czodrowski P, Krewald V, Hausch F Chem Sci. 2021 Nov 3;12(44):14758-14765. doi: 10.1039/d1sc04638a. eCollection, 2021 Nov 17. PMID:34820091 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also FKBP 3D structures

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