Constrained linear opioid peptides

Abstract

The immunosuppressive drug rapamycin works by binding together two proteins: the FK506 binding protein (FKBP12) and the FKBP-rapamycin associated protein (FRAP). The crystal structure of the immunosuppressive agent rapamycin complexed with human FK506 binding protein (FKBP12) and the FKBP12rapamycin binding domain (FRB) ofFKBP12-rapamycin associated protein (FRAP), reveals two proteins bound together through rapamycin's ability to simultaneously occupy two different hydrophobic binding pockets. FKBP12 has a hydrophobic binding pocket between a large !.\-sheet and a short amphipathic a-helix. FRB is a four-helix bundle, and the crossing region between two anti parallel helices fonns the rapamycin binding pocket. The structure shows extensive interactions between rapamycin and both proteins but only modest protein-protein interactions. The structure also provides, among other things, an understanding of the critical nature of the serine 2,035 residue, and the first structural information about the growing family of proteins related to the ataxia telangicetasia mutant (ATM) gene product. Crystals of the triple complex form in ~pace group P212121 with a= 44.63, b = 52.14, and c = 102.53 A and one FKBP12rapamycin-FRB complex in the asymmetric unit. Data were collected to 2. 7 A with a rotating anode source. A phasing model was found using !VIR (FKBP12) and SIRAS (HgCl2 derivative). The cunent model has R = 19.3% (Rfree = 29.9%) for the 6206 reflections between 8 and 2. 7 A and good geometry (r.m.s. deviations of o.oo8A for bond lengths and 1.48° for bond angles) for a model with 1639 protein atoms, 65 rapamycin atoms, and 23 solvent atoms-not counting hydrogens. MS05.01.02 THE RELEVANCE OF THE CRYSTAL STRUCTURE OF HUMAN ENDOTHELIN TOG-PROTEIN COUPLED RECEPTOR BINDING.