4W9Q

The Fk1 domain of FKBP51 in complex with (1S,5S,6R)-10-[(3,5-dichlorophenyl)sulfonyl]-3-[2-(3,4-dimethoxyphenoxy)ethyl]-5-ethyl-3,10-diazabicyclo[4.3.1]decan-2-one

Summary for 4W9Q

• Entry DOI: 10.2210/pdb4w9q/pdb
• Descriptor: Peptidyl-prolyl cis-trans isomerase FKBP5, (1S,5S,6R)-10-[(3,5-dichlorophenyl)sulfonyl]-3-[2-(3,4-dimethoxyphenoxy)ethyl]-5-ethyl-3,10-diazabicyclo[4.3.1]decan-2-one (3 entities in total)
• Functional Keywords: fk-506 binding domain, hsp90 cochaperone, immunophiline, peptidyl-prolyl isomerase, ligand selectivity, isomerase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: Q13451
• Total number of polymer chains: 1
• Total formula weight: 14597.59

Authors

Pomplun, S.,Wang, Y.,Kirschner, K.,Kozany, C.,Bracher, A.,Hausch, F. (deposition date: 2014-08-27, release date: 2014-12-03, Last modification date: 2024-01-10)

Primary citation

Pomplun, S.,Wang, Y.,Kirschner, A.,Kozany, C.,Bracher, A.,Hausch, F.
Rational Design and Asymmetric Synthesis of Potent and Neurotrophic Ligands for FK506-Binding Proteins (FKBPs).
Angew.Chem.Int.Ed.Engl., 54:345-348, 2015

PubMed Abstract: To create highly efficient inhibitors for FK506-binding proteins, a new asymmetric synthesis for pro-(S)-C(5) -branched [4.3.1] aza-amide bicycles was developed. The key step of the synthesis is an HF-driven N-acyliminium cyclization. Functionalization of the C(5)  moiety resulted in novel protein contacts with the psychiatric risk factor FKBP51, which led to a more than 280-fold enhancement in affinity. The most potent ligands facilitated the differentiation of N2a neuroblastoma cells with low nanomolar potency.

PubMed: 25412894
DOI: 10.1002/anie.201408776

Experimental method

X-RAY DIFFRACTION (1.08 Å)