7aou

The Fk1 domain of FKBP51 in complex with (2'R,5'S,12'R)-12'-cyclohexyl-2'-[2-(3,4-dimethoxyphenyl)ethyl]-3',19'-dioxa-10',13',16'-triazaspiro[cyclopropane-1,15'- tricyclo[18.3.1.0-5,10]tetracosane]-1'(24'),20',22'-triene-4',11',14',17'-tetrone

spinqualitylabelsall models 7aou, resolution 1.16Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7aou 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 1.16Å Ligands: RTT 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 Subtype selectivity represents a recurring challenge in many drug discovery campaigns. A typical example is the FK506 binding protein 51 (FKBP51), which has emerged as an attractive drug target for mood disorders, obesity and chronic pain. The most advanced FKBP51 ligands of the SAFit class are highly selective vs. FKBP52 but poorly discriminate against the homologs and off-targets FKBP12 and FKBP12.6. During a macrocyclization pilot study, we surprisingly observed that many of these macrocyclic analogs have unanticipated and unprecedented preference for FKBP51 over FKBP12 and FKBP12.6. Structural studies revealed that these macrocycles bind with a new binding mode featuring a transient conformation, which is disfavored for the small FKBPs. Using a conformation-sensitive assay we show that this binding mode occurs in solution and is characteristic for this new class of compounds. The discovered macrocycles are non-immunosuppressive, engage FKBP51 in cells, and block the cellular effect of FKBP51 on IKKalpha. Our findings provide a new chemical scaffold for improved FKBP51 ligands and the structural basis for enhanced selectivity. Macrocyclic FKBP51 ligands define a transient binding mode with enhanced selectivity.,Voll AM, Meyners C, Taubert MC, Bajaj T, Heymann T, Merz S, Charalampidou A, Kolos J, Purder PL, Geiger TM, Wessig P, Gassen NC, Bracher A, Hausch F Angew Chem Int Ed Engl. 2021 Apr 11. doi: 10.1002/anie.202017352. PMID:33843131 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also FKBP 3D structures

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