Atomic Structure of FKBP-FK506, an Immunophilin-Immunosuppressant Complex

• Published in: Science (American Association for the Advancement of Science) Vol. 252; no. 5007; pp. 839 - 842
• Main Authors: Van Duyne, Gregory D., Standaert, Robert F., Karplus, P. Andrew, Schreiber, Stuart L., Clardy, Jon
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for the Advancement of Science 10-05-1991; American Association for the Advancement of Science; The American Association for the Advancement of Science
• Subjects: Amides; Anti-Bacterial Agents - metabolism; Atomic structure; Atoms; Binding Sites; Biochemistry; Biological and medical sciences; Carrier Proteins - ultrastructure; Cell receptors; Electron density; Electronic structure; Enzymes; FK 506; Humans; Hydrogen bonds; Hydroxyls; Immunomodulators; Immunosuppressive Agents; Ligands; Medical sciences; Molecular mechanisms of action; Molecular Structure; Molecules; Pharmacology. Drug treatments; Protein binding; Proteins; Tacrolimus; Tacrolimus Binding Proteins; X ray diffraction; X-ray crystallography; Binding protein; Configuration; Molecular association; Molecular complex; Immunosuppressive agent; X ray diffraction; Bound form; Crystalline structure
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1709302

The structure of the human FK506 binding protein (FKBP), complexed with the immunosuppressant FK506, has been determined to 1.7 angstroms resolution by x-ray crystallography. The conformation of the protein changes little upon complexation, but the conformation of FK506 is markedly different in the bound and unbound forms. The drug's association with the protein involves five hydrogen bonds, a hydrophobic binding pocket lined with conserved aromatic residues, and an unusual carbonyl binding pocket. The nature of this complex has implications for the mechanism of rotamase catalysis and for the biological actions of FK506 and rapamycin.