Refined structure of the FKBP12-rapamycin-FRB ternary complex at 2.2 angstrom resolution

The structure of the FKBP12-rapamycin-FRB ternary complex has now been refi ned at 2.2 Angstrom resolution The cell-cycle arrest agent rapamycin binds FK506-binding protein (FKBP12) and the FKBP12-rapamycin binding (FRB) domai n of FKBP12-rapamycin associated protein (FRAP) simultaneously, and the inh ibition of FRAP is responsible for rapamycin's biological activity The conf ormation of rapamycin in the ternary complex is very similar to that observ ed in the FKBP12-rapamycin binary complex, with an r.m.s. difference of onl y 0.30 Angstrom. However, a slight (9 degrees) rotation repositions the FRB -binding face of rapamycin in the ternary complex. There are extensive rapa mycin-protein interactions and relatively few interactions between the two protein partners FKBP12 and FRB. these interactions mainly involving residu es in the 40s and 80s loops of FKBP12 and alpha 1 and alpha 4 of FRB. The h igh-resolution refinement has revealed the crucial role of several buried w aters in the formation of the ternary complex.