Selective inhibitors of the FK506-binding protein 51 by induced fit

Abstract

The FK506-binding protein 51 (FKBP51, encoded by the FKBP5 gene) is an established risk factor for stress-related psychiatric disorders such as major depression. Drug discovery for FKBP51 has been hampered by the inability to pharmacologically differentiate against the structurally similar but functional opposing homolog FKBP52, and all known FKBP ligands are unselective. Here, we report the discovery of the potent and highly selective inhibitors of FKBP51, SAFit1 and SAFit2. This new class of ligands achieves selectivity for FKBP51 by an induced-fit mechanism that is much less favorable for FKBP52. By using these ligands, we demonstrate that selective inhibition of FKBP51 enhances neurite elongation in neuronal cultures and improves neuroendocrine feedback and stress-coping behavior in mice. Our findings provide the structural and functional basis for the development of mechanistically new antidepressants.

Coupling of Conformational Transitions in the N-terminal Domain of the 51-kDa FK506-binding Protein (FKBP51) Near Its Site of Interaction with the Steroid Receptor Proteins

“…Introducing the analogous F67V mutation to the FK1 domains of FKBP51 and FKBP52, Hausch and colleagues (23) recently reported the development of FKBP51-selective inhibitors using Shield1 as their initial scaffold. In contrast to earlier studies on the F36V variant of FKBP12, which exhibited minimal structural perturbation upon inhibitor binding (51), Hausch and colleagues (23) found that their iFit inhibitors bound to a conformation of wild type FKBP51 and FKBP52 in which the Phe-67 side chain is reoriented away from its typical position packed underneath the tip of the ␤ 4 -␤ 5 loop (Fig. 2).…”

“…FKBP51-like substitutions, T58K or W60K, into FKBP52 yields a variant that binds the fluorescent iFit-FL ligand more tightly than does the wild type FKBP52 domain by over 100-fold, thus binding nearly as tightly as does FKBP51 (23). Conversely, introducing the K58T or the K60W mutation into FKBP51 markedly reduces the binding affinity for this ligand, consistent with a corresponding alteration in the stability of the conformation in the crystal structures of the iFit-inhibited protein.…”

“…Hausch and colleagues (23) have proposed that the altered conformation that they observed in their crystal structures of the iFit-inhibited FK1 domains is biochemically relevant. One line of potential support for that hypothesis comes from their demonstration that the introduction of either one of two (22)), in the iFit1-inhibited structure (green, PDB code 4TW6 (23)) the side chain of Phe-67 is reoriented out toward the solvent phase and the backbone of the ␤ 3a strand is shifted so as to enable a direct hydrogen bonding interaction between the amide of Asp-68 and the carbonyl oxygen of Gly-59.…”

“…In the year following our initial characterization of the conformational exchange line broadening dynamics surrounding the bifurcated main chain hydrogen bonding of the amides of Phe-67 and Asp-68 with the carbonyl oxygen of Gly-59, Hausch and colleagues (23) reported the crystal structures of two so-called iFit inhibitor-bound forms of the FK1 domain from FKBP51 in which the conformation of the ␤ 3a strand surrounding Phe-67 is altered so as to disrupt this bifurcated main chain hydrogen bonding interaction. They interpreted these structures to demonstrate an induced-fit mechanism of binding, despite the fact that the structure of the final ligand-bound state cannot discriminate between an induced-fit or a conformational selection-based mechanism (24).…”

Dissecting the molecular mechanisms of gene x environment interactions: implications for diagnosis and treatment of stress-related psychiatric disorders

“…It could be possible that patients suffering from such an FKBP5 disinhibition, but presenting with distinct psychiatric symptoms, could benefit from blocking FKBP5 activity. A selective high-affinity antagonist for FKBP5 has been developed, and first experiments in experimental animals show that is has anxiolytic effects and increases stress coping (Gaali et al, 2015; Hartmann et al, 2015). …”