X-ray crystallography suggests the C23-C28 segment of rapamycin may act more as an element of the FKBP binding domain than as part of the immunosuppressant effector domain. Selective excision of this region from the natural product followed by minor reconstruction of the binding domain resulted in compounds with high affinity for FKBP but no immunosuppressive activity. This, along with data from other secorapamycin analogs, suggest the importance of C23C28 in the orientation of the effector domain.