Abstract
In recent years, many members of the FK506-binding protein (FKBP) family were increasingly linked to various diseases. The binding domain of FKBPs differs only in a few amino acid residues, but their biological roles are versatile. High-affinity ligands with selectivity between close homologs are scarce. This review will give an overview of the most prominent ligands developed for FKBPs and highlight a perspective for future developments. More precisely, human FKBPs and correlated diseases will be discussed as well as microbial FKBPs in the context of anti-bacterial and anti-fungal therapeutics. The last section gives insights into high-affinity ligands as chemical tools and dimerizers.
Highlights
FK506-binding proteins (FKBPs) belong to the immunophilin family
The crystal structures give an insight in the different binding to human FKBP25 (hFKBP25), but further experiments are necessary to evaluate the role of Lys170
FKBP research has historically focused on human FKBP12, but more recently several other homologs have received increasing attention (e.g., FKBP12.6, FK506-binding protein 51 (FKBP51), aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1))
Summary
Like other immunophilins many FKBPs possess a cis-trans peptidyl-prolyl isomerase (PPIase) activity They can act as a co-receptor for the natural products FK506 and Rapamycin. The FKBP12-FK506 complex (depicted in Figure 1C) binds calcineurin (Griffith et al, 1995), a key enzyme in T-cell activation (Rosen and Schreiber, 1992; Kissinger et al, 1995), while the FKBP12-Rapamycin complex binds to the FKBP Rapamycin binding (FRB) domain of the mammalian target of Rapamycin (mTOR) (Liang et al, 1999; Banaszynski et al, 2005), a kinase involved in cell growth and cell proliferation (Waickman and Powell, 2012) Inhibition of both pathways leads to an immunosuppressive response. ElteN378 was developed by Martina et al and reported to have a Ki value of 3 nM determined by a fluorescent quenching assay (Martina et al, 2013)
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