Molecular modeling of human granulocyte‐macrophage colony‐stimulating factor

The colony‐stimulating factors (CSFs) are a group of acidic glycoproteins which are required for the proliferation of hematopoietic progenitor cells and for their differentiation into mature blood cells. Receptors for granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) are present on a wide spectrum of cells including erythroid, mixed erythroid‐non‐erythroid, mixed myeloid and megakaryocytic progenitors, and on mature neutrophils, eosinophils and monocytes. A number of studies are now available which provide insights into the structure‐function relationships of human GM‐CSF. In an attempt to further understand the interaction between GM‐CSF and its cell surface receptor, we have constructed models of the tertiary structure of human GM‐CSF using the known disulfide bonding pattern, predictions of the secondary structure of the growth factor and a model based on conformational homologies among cytokines (Parry et al., J Mol Recognition 1988;1:107–110). When compared to a number of functional mapping studies, structural features of the model are consistent with the experimental data, and the model, in turn, leads to the generation of a number of testable hypotheses. The implications of these features in terms of receptor‐ligand interaction are discussed.