Solution structure of the major binding protein for the immunosuppressant FK506

• Published in: Nature (London) Vol. 351; no. 6323; pp. 248 - 250
• Main Authors: Moore, Jonathan M, Peattie, Debra A, Fitzgibbon, Matthew J, Thomson, John A
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 16-05-1991
• Subjects: Amino acids; Biochemistry; Carrier Proteins - chemistry; Carrier Proteins - isolation & purification; Enzymatic activity; Humans; Lymphocytes; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Structure; Molecules; Proteins; Solutions - chemistry; Tacrolimus Binding Proteins
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/351248a0

The major FK506 binding protein (FKBP, relative molecular mass approximately 11,800; Mr 11.8K) and cyclophilin (Mr approximately 17K) belong to a class of proteins termed immunophilins. Although unrelated at the amino-acid sequence level, they both possess peptidyl-prolyl cis-trans isomerase activities which are inhibited by immunosuppressants that block signal transduction pathways leading to T-lymphocyte activation. FK506 and rapamycin strongly inhibit the peptidyl-prolyl cis-trans isomerase activity of FKBP, whereas cyclosporin A inhibits that of cyclophilin. The significance of this enzyme activity and the role of the immunophilins in immunoregulation is unknown. To understand better the function of the immunophilins and their interaction with inhibitors, we are investigating the solution structures of FKBP and FKBP-inhibitor complexes by multidimensional NMR methods. Here we report the solution conformation of FKBP, as generated by NMR, distance geometry and molecular dynamics methods. The regular secondary structure of FKBP is composed mainly of beta sheet (approximately 35%) with little helical structure (less than 10%). The hydrophobic core of the molecule, containing the buried side chains of six of the protein's nine aromatic amino acids, is enclosed by a five-stranded antiparallel beta sheet on one side, a loop and a short helix at residues 51-56 and 57-65, and an aperiodic loop at residues 81-95. Examination of the structure suggests a possible site of interaction with FK506.