MKHHHHHHAS MTTDEGAKNN EESPTATVAE QGEDITSKKD RGVLKIVKRV GNGEETPMIG DKVYVHYKGK LSNGKKFDSS HDRNEPFVFS LGKGQVIKAW DIGVATMKKG EICHLLCKPE YAYGSAGSLP KIPSNATLFF EIELLDFKGE DLFEDGGIIR RTKRKGEGYS NPNEGATVEI HLEGRCGGRM FDCRDVAFTV GEGEDHDIPI GIDKALEKMQ REEQCILYLG PRYGFGEAGK PKFGIEPNAE LIYEVTLKSF EKAKESWEMD TKEKLEQAAI VKEKGTVYFK GGKYMQAVIQ YGKIVSWLEM EYGLSEKESK ASESFLLAAF LNLAMCYLKL REYTKAVECC DKALGLDSAN EKGLYRRGEA QLLMNEFESA KGDFEKVLEV NPQNKAARLQ ISMCQKKAKE HNERDRRIYA NMFKKFAEQD AKEEANKAMG KKTSEGVTNE KGTDSQAMEE EKPEGHV.
FKBP5 is a cis-trans prolyl isomerase that binds to the immunosuppressants tacrolimus (FK506) and sirolimus (rapamycin) . It mediates calcineurin inhibition, which is essential for its immunosuppressive properties . FKBP5 also interacts functionally with mature corticoid receptor hetero-complexes, including progesterone, glucocorticoid, and mineralocorticoid receptor complexes, along with the 90 kDa heat shock protein (Hsp90) and PTGES3 (P23 protein) .
As an Hsp90-associated co-chaperone, FKBP5 regulates the responsiveness of steroid hormone receptors, playing a significant role in stress endocrinology and glucocorticoid signaling .
FKBP5 is an attractive drug target due to its involvement in several diseases, including stress-related disorders, chronic pain, and obesity . SAFit2, a well-characterized FKBP51 ligand, has shown promising effects in numerous animal models . Macrocyclic FKBP51-selective ligands are non-immunosuppressive, engage FKBP51 in cells, and block the cellular effect of FKBP51 .
Comparative analysis of FKBP family proteins reveals that the eight known Drosophila FKBPs share homology with the human FKBP12, indicating a close evolutionary relationship . The known FKBPs contain FK domains, which are prolyl cis/trans isomerase (PPIase) domains that mediate immune suppression through inhibition of calcineurin .