CRYSTAL-STRUCTURE AT 2.6-ANGSTROM RESOLUTION OF HUMAN MACROPHAGE-MIGRATION INHIBITORY FACTOR

Macrophage migration inhibitory factor (MIF) was the first cytokine to be described, but for 30 years its role in the immune response remain ed enigmatic. In recent studies, MIF has been found to be a novel pitu itary hormone and the first protein identified to be released from imm une cells on glucocorticoid stimulation. Once secreted, MIF counterreg ulates the immunosuppressive effects of steroids and thus acts as a cr itical component of the immune system to control both local and system ic immune responses. We report herein the x-ray crystal structure of h uman MIF to 2.6-Angstrom resolution. The protein is a trimer of identi cal subunits. Each monomer contains two antiparallel alpha-helices tha t pack against a four-stranded beta-sheet. The monomer has an addition al two beta-strands that interact with the beta-sheets of adjacent sub units to form the interface between monomers. The three beta-sheets ar e arranged to form a barrel containing a solvent-accessible channel th at runs through the center of the protein along a molecular 3-fold axi s. Electrostatic potential maps reveal that the channel has a positive potential, suggesting that it binds negatively charged molecules. The elucidated structure for MIF is unique among cytokines or hormonal me diators, and suggests that this counterregulator of glucocorticoid act ion participates in novel ligand-receptor interactions.