THE STRUCTURE OF GRANULOCYTE-COLONY-STIMULATING FACTOR AND ITS RELATIONSHIP TO OTHER GROWTH-FACTORS

We have determined the three-dimensional structure of recombinant huma n granulocyte-colony-stimulating factor by x-rav crystallography. Phas es were initially obtained at 3.0-angstrom resolution by multiple isom orphous replacement and were refined by solvent flattening and by aver aging of the electron density of the three molecules in the asymmetric unit. The current R factor is 21.5% for all data between 6.0- and 2.2 -angstrom resolution. The structure is predominantly helical, with 104 of the 175 residues forming a four-alpha-helix bundle. The only other secondary structure is also helical. In the loop between the first tw o long helices a four-residue 3(10)-helix is immediately followed by a 6-residue alpha-helix. Three residues in the short connection between the second and third bundle helices form almost one turn of left-hand ed helix. The up-up-down-down connectivity with two long crossover con nections has been reported previously for five other proteins, which l ike granulocyte-colony-stimulating factor are all signaling ligands: g rowth hormone, granulocyte/macrophage-colony-stimulating factor, inter feron beta, interleukin 2, and interleukin 4. Structural similarity am ong these growth factors occurs despite the absence of similarity in t heir amino acid sequences. Conservation of this tertiary structure sug gests that these different growth factors might all bind to their resp ective sequence-related receptors in an equivalent manner.