title: Structure-based design of a cyclophilin-calcineurin bridging ligand.
abstract: The affinity of a flexible ligand that adopts a specific conformation when bound to its receptor should be increased with the appropriate use of conformational restraints. By determining the structure of protein-ligand complexes, such restraints can in principle be designed into the bound ligand in a rational way. A tricyclic variant (TCsA) of the immunosuppressant cyclosporin A (CsA), which inhibits the proliferation of T lymphocytes by forming a cyclophilin-CsA-calcineurin complex, was designed with the known three-dimensional structure of a cyclophilin-CsA complex. The conformational restraints in TCsA appear to be responsible for its greater affinity for cyclophilin and calcineurin relative to CsA.
authors.affiliation: Department of Chemistry, Harvard University, Cambridge, MA 02138.
authors.forename: D G
authors.initials: DG
authors.lastname: Alberg
authors.forename: S L
authors.initials: SL
authors.lastname: Schreiber
mesh_terms: D000591:Amino Acid Isomerases / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D019703:Calcineurin; D002148:Calmodulin-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D003524:Cyclosporins / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D019696:Peptidylprolyl Isomerase; D010749:Phosphoprotein Phosphatases / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation
chemical_list: D002148:Calmodulin-Binding Proteins; D002352:Carrier Proteins; D003524:Cyclosporins; D008024:Ligands; C083555:tricyclic cyclosporin A; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D000591:Amino Acid Isomerases; D019696:Peptidylprolyl Isomerase