Crystal packing reveals rapamycin-mediated homodimerization of an FK506-binding domain

Chemically induced dimerization (CID) is used to induce proximity and result in artificial complex formation between a pair of proteins involved in biological processes in cells to investigate and regulate these processes. The induced heterodimerization of FKBP fusion proteins by rapamycin and FK506 has been extensively exploited as a chemically induced dimerization system to regulate and understand highly dynamic cellular processes. Here, we report the crystal structure of the AtFKBP53 FKBD in complex with rapamycin. The crystal packing reveals an unusual feature whereby two rapamycin molecules appear to mediate homodimerization of the FKBD. The triene arm of rapamycin appears to play a significant role in forming this dimer. This forms the first structural report of rapamycin-mediated homodimerization of an FKBP. The structural information on the rapamycin-mediated FKBD dimerization may be employed to design and synthesize covalently linked dimeric rapamycin, which may subsequently serve as a chemically induced dimerization system for the regulation and characterization of cellular processes.

Automated summary

Chemically induced dimerization is a method used to regulate cellular processes by inducing close proximity between proteins. The heterodimerization induced by rapamycin and FK506 is commonly used to study dynamic cellular processes. The crystal structure of the AtFKBP53 FKBD in complex with rapamycin reveals that rapamycin can mediate homodimerization of FKBD, providing insights for the design of chemically induced dimerization systems.