5OBK

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

Summary for 5OBK

• Entry DOI: 10.2210/pdb5obk/pdb
• Descriptor: Peptidyl-prolyl cis-trans isomerase FKBP5, (1~{S},5~{S},6~{R})-10-[3,5-bis(chloranyl)phenyl]sulfonyl-5-(hydroxymethyl)-3-(pyridin-2-ylmethyl)-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: 14510.47

Authors

Pomplun, S.,Sippel, C.,Haehle, A.,Bracher, A.,Hausch, F. (deposition date: 2017-06-28, release date: 2018-04-04, Last modification date: 2024-01-17)

Primary citation

Pomplun, S.,Sippel, C.,Hahle, A.,Tay, D.,Shima, K.,Klages, A.,Unal, C.M.,Riess, B.,Toh, H.T.,Hansen, G.,Yoon, H.S.,Bracher, A.,Preiser, P.,Rupp, J.,Steinert, M.,Hausch, F.
Chemogenomic Profiling of Human and Microbial FK506-Binding Proteins.
J. Med. Chem., 61:3660-3673, 2018

PubMed Abstract: FK506-binding proteins (FKBPs) are evolutionarily conserved proteins that display peptidyl-prolyl isomerase activities and act as coreceptors for immunosuppressants. Microbial macrophage-infectivity-potentiator (Mip)-type FKBPs can enhance infectivity. However, developing druglike ligands for FKBPs or Mips has proven difficult, and many FKBPs and Mips still lack biologically useful ligands. To explore the scope and potential of C-substituted [4.3.1]-aza-bicyclic sulfonamides as a broadly applicable class of FKBP inhibitors, we developed a new synthesis method for the bicyclic core scaffold and used it to prepare an FKBP- and Mip-focused library. This allowed us to perform a systematic structure-activity-relationship analysis across key human FKBPs and microbial Mips, yielding highly improved inhibitors for all the FKBPs studied. A cocrystal structure confirmed the molecular-binding mode of the core structure and explained the affinity gained as a result of the preferred substituents. The best FKBP and Mip ligands showed promising antimalarial, antileginonellal, and antichlamydial properties in cellular models of infectivity, suggesting that substituted [4.3.1]-aza-bicyclic sulfonamides could be a novel class of anti-infectives.

PubMed: 29578710
DOI: 10.1021/acs.jmedchem.8b00137

Experimental method

X-RAY DIFFRACTION (1 Å)