Structural and biochemical insights into FKBP51 as a Hsp90 co‐chaperone

Abstract

The FK506‐binding protein 51 (FKBP51) is a high‐molecular‐weight immunophilin that emerged as an important drug target for stress‐related disorders, chronic pain, and obesity. It has been implicated in a plethora of molecular pathways but remains best characterized as a co‐chaperone of Hsp90 in the steroid hormone receptor (SHR) maturation cycle. However, the mechanistic and structural basis for the regulation of SHRs by FKBP51 and the usually antagonistic function compared with its closest homolog FKBP52 remains enigmatic. Here we review recent structural and biochemical studies of FKBPs as regulators in the Hsp90 machinery. These advances provide important insights into the roles of FKBP51 and FKBP52 in SHR regulation.

Entdeckung eines potenten PROTAC ermöglicht die gezielte Ausschaltung der Gerüstfunktionen von FKBP51

“…[2][3][4][5] Das FK506-bindende Protein 51 (FKBP51) ist ein Co-Chaperon in der Hsp90-Maschinerie und ein Schlüsselregulator der Steroidhormonsignalwege. [6] Besonders im Kontext des Glukokortikoidrezeptors (GR) wirkt FKBP51 in einer ultraschnellen Rückkopplungsschleife, um die Aktivierung der Hypothalamus-Hypophysen-Nebennierenrindenachse zu kontern und die Stressreaktion fein zu regulieren. [7] In den letzten Jahren wurde FKBP51 als vielversprechendes Wirkstoffziel für stressbedingte psychiatrische Störungen, [8,9] chronischen Schmerz [9][10][11][12][13] und Fettleibigkeit [14][15][16][17] identifiziert.…”

Discovery of a Potent Proteolysis Targeting Chimera Enables Targeting the Scaffolding Functions of FK506‐Binding Protein 51 (FKBP51)

“…[2][3][4][5] The FK506-binding protein 51 (FKBP51) is a cochaperone in the Hsp90 machinery and a key regulator of steroid hormone signalling. [6] Especially in the context of the glucocorticoid receptor (GR), FKBP51 acts in an ultra-short feedback loop to counteract the hypothalamic-pituitary-adrenal axis activation and fine-tune the stress response. [7] In recent years, FKBP51 emerged as a promising drug target for stressrelated mental disorders, [8,9] chronic pain, [9][10][11][12][13] and obesity.…”